The Importance of Dietary Fatty Acid Balance

Cell Membranes, Endothelia, and Atherosclerosis – The Importance of Dietary Fatty Acid Balance

Parris M. Kidd, Ph.D.

Abstract Atherosclerosis begins at the fragile blood vessel endothelia, which may be the Achilles’ Heel of the circulation. The endothelia are thin cell sheets vulnerable to injury, yet from their cell membranes come fatty acid metabolites (prostanoids, other eicosanoids) that coordinate vessel wall homeostasis and help protect against atherosclerosis. Oxidation products of fatty foods threaten endothelial integrity, and dietary fatty acids protected by dietary antioxidants can slow or perhaps even reverse atherosclerosis. Eicosanoid messenger molecules, generated from 20-carbon fatty acids associated with membrane phospholipids, are among the major factors ensuring vessel wall homeostasis. Among their functions is to help control blood vessel tone, retard platelet aggregation, and discourage white blood cells and platelets from adhering to the vessel wall. Eicosanoid balance is delicately poised between anti-inflammation and pro-inflammation, with the dietary intake of fatty acids and antioxidants influencing this balance. The 2-series metabolites from arachidonic acid are quantitatively the most abundant, while the 1-series (from DGLA) and the 3-series (from EPA) counter- balance the 2-series and enhance atherosclerosis protection and heart disease prevention. Dietary long-chain, unsaturated fatty acids also benefit the blood vessel wall by enhancing cell membrane fluidity and regulating membrane receptors. Inconsistent clinical results with the dietary fatty acids may be related to dose. High doses of any one of the n-3, n-6, or n-9 FAs may create deficiencies of others. For consistent, effective nutritional support against atherosclerosis, a diversified intake of fatty acids should only be undertaken in conjunction with a generous intake of antioxidants. (Alt Med Rev 1996;1(3):148-167.)

Atherosclerosis continues to be the major killer disease of Western society. After in- tense research efforts that have spanned decades, a consensus is emerging that the major caus- ative factors in atherosclerosis are oxidized breakdown products of dietary fats.1-3 But fats cannot simply be excluded from the diet, most especially because of the essential fatty acids. These function much as vitamins function, fitting the classic deficiency yardstick for vitamins.5 This review is an effort to sort out the potential contributions of the essential fatty acids to the prevention and management of atherosclerosis through a critical assessment of their respective roles in blood vessel homeostasis. Because the literature on atherosclerosis is so massive, only initiation and the earlier stages of progression will be considered in detail.

FA =Fatty acid Balance tty Acid EFA = Essential fatty acid PUFA = Polyunsaturated fatty acid Atherosclerosis ini- Eicosanoids = Metabolites of cell membrane fatty acids; includes prostanoids tiation and early progression (PGs, Txs) + peroxide metabolites + leukotrienes is almost invariably a result Prostanoids = Prostaglandins (PGs) and thromboxanes (Txs), metabolites of of abnormal interactions be- cell membrane 20-carbon fatty acids via cyclo-oxygenase tween circulating oxidized OxLDL = oxidized low-density lipoproteins lipids and the blood vessel OxChol = oxidized cholesterol derivatives walls.1-6 White blood cells n-6 = omega-6 fatty acid, first double bond at the 6th carbon after (monocytes, macrophages) the methyl group n-3 = omega-3 fatty acid, first double bond at the 3rd carbon after and platelets tend to become the methyl group involved subsequent to the n-9 = omega-9 fatty acid, first double bond at the 9th carbon after initial damaging event. The the methyl group pivotal target zone for athero- AA =arachidonic acid, 20 carbons, 4 double bonds, omega-6. (C20:4 sclerosis initiation is the en- n-6) Precursor to the 2-series prostanoids dothelial system that lines all DGLA = dihomo-gamma-linolenic acid, 20 carbons, 3 double bonds, blood vessels.3,4 Situated at (C20:3 n-6) omega-6. Precursor to the 1-series prostanoids the vital interface between GLA = gamma-linolenic acid, 18 carbons, 3 double bonds, omega-6 (C18:3 n-6) the circulating blood and the LA = linoleic acid, 18 carbons, 2 double bonds, omega-6. Precur- deeper layers of the vessel sor to (C18:2 n-6) the eicosanoid 13-HODE via 15- wall, the endothelia are thin lipoxygenase sheets of flattened cells. Be- EPA = eicosapentaenoic acid, 20 carbons, 5 double bonds, omega-3. ing only one cell thick, the (C20:5 n-3) Precursor to the 3-series prostanoids endothelial sheet is delicate DHA = docosahexaenoic acid, 22 carbons, 6 double bonds, omega-3 and is extremely vulnerable (C22:6 n-3) to physical or chemical at- OA = oleic acid, 18 carbons, 1 double bond, omega-9 (C18:1 n-9) PG, Tx = prostaglandins, thromboxanes (prostanoids) tack. The fragility of the vessel wall endothelia may be the Achilles’ Heel of the circulation as a whole. endothelium must first have been breached by some injurious agent. Endothelial Dysfunction is A small gap between adjoining endot- Linked to Atherosclerosis helial cells, or the stripping away of a stretch of endothelium (“denudation”) can allow oxi- Endothelial dysfunction or disruption dized LDL or other oxidants into the vessel has been linked to diverse vascular abnormali- wall.1 The exposed subendothelial wall is ties, including vasospasm, intimal hyperpla- “sticky,” and as the sheet is interrupted white sia, coagulopathies, and microcirculatory dys- cells begin to approach the area and attach by functions (see Figure 1), in addition to the “Big way of adherence receptors.6 An inflamma- 3”—diabetes, hypertension, and atherosclero- tory focus is initiated, and after inflammatory sis.1-4 cytokine messengers are produced, smooth The first detectable stage in atheroscle- muscle cells begin to proliferate out of con- rosis is a slightly raised, fatty “streak” in the trol. The inflammatory cascade worsens, and arterial wall.1 Among Western populations, eventually a chronic inflammatory, atheroscle- these can be found in most individuals begin- rotic lesion is established in the vessel wall.1,2 ning as early as the teenage years. The fatty Vulnerable as they may be, the en- streak is much like a localized inflammatory dothelia do possess biochemical defense response to the “wounding” of a vessel wall.2 mechanisms, which fall into two major But for a fatty streak to develop, the vessel

Diabetes Hypertension

Sepsis Endothelium Microcirculatory Dysfunction

Coagulopathies Vasospasm Inflammation Ischemia Smooth Muscle Reperfusion Cell Proliferation Injury

Intimal Hyperplasia

FIGURE 1.

meostasis, provides a thin line of defense for classes: antioxidant defenses, and “prostag- the deeper segments of the vessel wall, and landin” (really prostanoid) cascades that origi- after damage has occurred, coordinates heal- nate from membrane fatty acids. These two ing of the wall. When functioning optimally, classes of endothelial defense have extensive the endothelial system is intensely active. It biochemical-metabolic overlap, and are tightly maintains a moment-to-moment, delicately- intertwined in their support of blood vessel poised, homeostatic balance in the blood ves- homeostasis. Since antioxidant defense sel networks. The system functions to control mechanisms are more generally understood at vessel tone and to manage inflammatory cas- this point, herein a more detailed emphasis will cades initiated in response to injury. be placed on the fatty acid defenses. By producing and releasing multiple Horrobin recently published5 a well- messenger factors, the endothelial sheet main- reasoned proposal that “the causes of vascu- tains (a) a state of relative vasodilation of the lar disease are abnormal membrane phospho- vessel wall, mediated by the smooth muscle; lipid concentrations of the 20-carbon and 22- (b) a state of “anti-adherence” to white blood carbon essential fatty acids (EFAs) of the n-6 cells, delicately balanced and able to quickly and n-3 series.” He makes a persuasive case shift to pro-adherence in case of injury; (c) that abnormal levels of these fatty acids are relative growth inhibition of the smooth muscle predictive of death from coronary heart dis- cells deeper in the wall, able to shift to growth ease (CHD), by demonstrating that in con- promotion in response to injury; and (d), an trolled trials provision of the EFAs or their anti-coagulation state of the platelets, also longer-chain derivatives reduced mortality. poised to quickly shift to procoagulation once The likely focus for the protective actions of the vessel wall becomes damaged.3, 4 the EFAs is the vessel endothelia. The endothelial system must continually be in a state of readiness to cope with Endothelial Homeostasis threats to its integrity—once its thin sheet has and Defense Mechanisms been breached, the deeper layers of the vessel The 5,000 square meters of endothelia wall lie naked and vulnerable. Unfortunately, that line the blood vessels of the adult human modern living features an array of stressors are 1% of the body’s mass and function virtu- that can injure, damage, or poison the endot- ally as an organ.4 They make up a vessel en- helial system. dothelial system that manages blood vessel ho-

tty Acid Balance tty Acid

Life Stressors and Endothelial to appropriate stimulation. This is part and Protective Mechanisms parcel of the normal inflammatory cascade, but Damage to the blood vessel endothe- even under favorable conditions the cascade lium is more or less an obligatory step in the is finely poised. In a situation of oxidant ex- development of atherosclerotic vascular dis- cess or prostanoid imbalance, pro-inflamma- ease. Sources of damage to the arterial endot- tory mediators can escape homeostatic con- helium include: trol and create havoc in the vessel wall. Oxidized serum lipids. The circulat- Circulating “free radical” and other 7-10 ing lipoproteins in undisturbed native form do oxidant toxins. Foremost among these are not appear to be significantly irritant or toxic the myriad oxidant substances from cigarette to the endothelium; rather, oxidized low-den- smoke, but also included are pesticides and sity lipoproteins (OxLDL) and oxidized de- herbicides, solvents, and many pharmaceuti- rivatives of cholesterol (OxChol) are the main cals. Oxygen radicals produced endogenously offenders.1-4 Oxidative damage to the endo- from respiration—superoxide, hydrogen per- thelial sheet lowers endothelial barrier func- oxide, hydroxyl—also can cause damage when tion and increases access of toxic agents to the they escape intrinsic antioxidant defenses underlying smooth muscle cells. As the sub- and accumulate to excess. Auto-oxidation endothelial layers become involved, control products of circulating catecholamines, pro- over the growth of the smooth muscle cells duced from ongoing emotional stress, may becomes lost, and their proliferation drives the add to the free radical/oxidant burden of the development of an atherosclerotic lesion. circulating blood. 8 Turbulent blood flow.3,4 The endot- Hyperglycemia. Glucose circulating helial cells are mechanosensors, and can trans- in the blood can undergo an oxidation-type duce the physical forces produced by the blood reaction with amino groups of proteins. This flow into biochemical signals to which the results in highly crosslinked AGE (advanced vessel wall can respond. Both rapid and glycosylation endproducts) which can gum up longer-term responses are engineered by the metabolism. AGE have strong oxidant char- endothelia. A disrupted zone of endothelium acter, and have been linked to the produc- can create blood flow turbulence, which then tion of vasoconstrictive prostanoids and oxy- excerbates damage at this vulnerable site or gen free radicals. Diabetics characteristi- elsewhere. cally carry high blood AGE, and endothe- Angioplasty and vessel grafting.3,4 lial dysfunction is an intrinsic feature of dia- These procedures both result in endothelial betic blood vessel disease. 3, 9,10 damage, the former as a direct result of the Nutrient imbalances. Probably mechanical “artero-rooter” invasion of the the most severe nutrient imbalance for the cir- vessel and the latter due to deterioration of the culation is homocysteine buildup. Homocys- endothelium during the course of its removal teine is a sulfur amino acid, an oxidized me- and re-placement. In the second case, athero- tabolite of methionine. As an essential amino sclerosis in the grafted vessel commonly oc- acid, methionine is a precursor molecule for curs; sometimes the grafted vessel heals itself, many metabolic pathways, and is continually and sometimes an “accelerated atherosclero- in a metabolic balance with homocysteine. sis” occurs that quickly results in re-stenosis. The latter can be recycled back to methion- Inflammatory mediators.1-4 A vari- ine, but only if vitamins B6, B12, and folate ety of these are carried in the circulating white are available. In the absence of all or any of these cells and in platelets, to be released in response required metabolic cofactors, homocysteine

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 151 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission builds up in the circulating blood and becomes of the known oxygen radicals. Superoxide toxic to the vessel wall. radicals can cause the release of stored iron Other toxins or circulating irritants. and exacerbate the Fenton reaction. These include alcohol, heavy metals, infec- Membrane phospholipids and asso- tious agents that reach the circulation, toxins ciated essential fatty acids.5,56 Every living produced by infectious agents located else- cell has to maintain homeostasis internally where (as in the gut), and a myriad of natural while being responsive to stresses or messages or manufactured allergenic substances. from the outside. The outermost membrane The health of the blood vessel wall is (called the cell membrane) is a sorting-switch- a net outcome of complex interactions between ing-signalling complex, a master switch for the the various toxic and protective factors that im- cell. The cell membrane controls (a) the entry pinge upon it. Endothelial protective factors of nutrients into the cell and the exit of waste fall into the following classes: endproducts; (b) ion movements, acidity-al- Intrinsic antioxidant factors.3,7,10-17 kalinity, and oxidation-reduction (redox) state Healthy endothelial cells carry a substantial inside the cell; (c) the passage of molecular complement of antioxidant factors, including messages into and out of the cell; (d) shape ascorbate (C), tocopherol (E), and glutathione, changes, expansion, and mobility of the cell; as well as the enzymes superoxide dismutase, and (e) the cell’s capacities to identify, com- catalase, and those that synthesize, utilize, and municate with, and associate with other cells. recycle glutathione. Selenium, an essential The membrane components which mineral cofactor for the enzyme glutathione manage these master switch activities are the peroxidase, in conjunction with glutathione ion pumps, transport molecules, enzymes, and and vitamin E helps keep down the levels of receptors, and all are mostly protein in nature. peroxides that threaten the endothelium. Zinc For the membrane to function at its best, each is both an antioxidant enzyme cofactor and a of these molecules must be provided with just stabilizer of cell membranes. It is vital to en- the right mix of fluidity, charge, and redox state dothelial integrity, and may also protect against (antioxidation/oxidation balance).56 Phospho- the potent, pro-inflammatory PAF (platelet lipids and a small amount of cholesterol make activating factor). Copper, an essential cofac- up the membrane matrix, and fatty acids asso- tor for superoxide dismutase (SOD), is pro- ciated with the phospholipids help integrate tective at low levels but can become pro-in- these proteins into the membrane. As a result, flammatory at higher levels. Extracellular signalling both from the outside of the cell SOD occurs at very high levels in the healthy inward and from the inside of the cell outward blood vessel walls. is subject to control by the phospholipids and Magnesium is not known as an anti- their associated fatty acids. oxidant cofactor, yet its deficiency can exac- Prostanoids (prostaglandins and erbate atherosclerosis progression.10 Endot- thromboxanes).5,19-20 These are a class of helial cells when depleted of magnesium pro- physiological effector molecules chemically duce peroxides that can result in the cells’ self- related to the 20-carbon prostanoic acid, which destruction. Iron buildup in the blood, to a technically is 7-[2-(1-Octanyl)cyclopentyl] point where it exceeds the buffering capacity heptanoic acid. The term “prostaglandin” was of transferrin and other proteins, can facilitate coined for these substances because their ac- a classic Fenton Reaction.10 This reaction can tivity was first noted in the prostate gland and transform the relatively benign hydrogen per- first characterized in semen.20 “Prostanoids” oxide into hydroxyl radical, the most reactive is a term that includes both the prostaglandins

tty Acid Balance tty Acid Nutrient Oxidative Imbalance Stress

(PG) and the thromboxanes (Tx), which tend Antiatherogenic/Antioxidant to have opposing biological actions. The Nutrients broader term “eicosanoids” encompasses per-

oxides and leukotrienes as well as PGs and Endothelial Cell Injury/Dysfunction Txs, all derived from cell membrane fatty acids. Endothelium-derived relaxing fac- 3,4 ¥ Platelet Aggregation and Adhesion tor (EDRF), and nitric oxide (NO). These ¥ Leukocyte Adhesion are small molecules that share many of the va- ¥ Vascular Tone Regulation ¥ Coagulation and Fibrinogenesis soactive properties of the PGI2/prostacyclin, since they relax smooth muscle and inhibit platelet aggregation. The best-understood re- Atherosclerosis laxing factor is nitric oxide (NO), which is biosynthesized by the enzymatic conversion of l-arginine. A minimum of 5 cofactors are FIGURE 2. required for this pathway, including nicotina- mide adenine dinucleotide phosphate (NADP), tained between the fluxes of prostacyclins ver- tetrahydrobiopterin, flavin adenine nucleotide sus thromboxanes, and between NO and oxy- (FAD), flavin mononucleotide (FMP), and gen free radicals, and with other factors so as heme. NO acts by stimulating cell membrane to maintain a healthy vascular tone. Oxida- guanylate cyclase, which then raises cyclic tive attack or other events that disrupt this com- GMP inside the cell. plex “yin-yang” equilibrium can lead to blood NO does not carry all EDRF activity. cell (platelet-monocyte-neutrophil) adherence, Other metabolites of NO such as thiols (sulf- release of a variety of vasoconstrictive factors,4 hydryls, cysteine-derived) appear to have and a shift away from homeostasis towards po- EDRF activity, and EDHFs (endothelium-de- tentially pathophysiologic consequences.18-23 rived hyperpolarization factors) such as ace- tylcholine and other chemical transmitters ac- Oxidized Lipids Trigger count for some of the rest. Also, recent findings suggest that NO is not unconditionally Atherosclerosis protective for the endothelia—toxic influences While any of the aforementioned can convert NO into a potentially toxic mol- sources of endothelial damage can exacerbate ecule. EDRF/NO activity can be protected by pre-existing damage and thereby speed athero- the antioxidant enzyme superoxide dismutase, sclerosis progression, a growing body of evi- but is subject to destruction by oxygen free dence indicts oxidant/free radical agents as the 1-4 radicals. major initiators of vessel wall damage. The Longer-term regulators of endothe- most common sources of such oxidants/free lial activity.3,4 These include (a) the radicals are foods—frying oils, precooked endothelins, (b) locally-produced renins and meat products, dried dairy and egg products, angiotensins, and (c) bradykinin. All three of margarine and butter, and any food with sub- these classes of peptide regulatory substances stantial content of rancid fats. As they reach act mainly through the prostanoid cascades of the bloodstream, oxidized food derivatives the endothelia. pose a direct threat to the vessel endothelia Under optimal conditions, along every (see Figure 2). endothelial segment a delicate balance is main-

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 153 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission However minor and localized the in- small amounts. Interestingly, saturated FAs jury, any interruption of the endothelial cell (C16:0, C18:0) were not toxic to the endothe- sheet is likely to reduce its effectiveness in pro- lia in these experiments. tecting the deeper vessel wall.3,4,21-24 Among This pessimistic picture of the poten- the major agents threatening the endothelia are tial of peroxidized EFAs to cause destruction the polyunsaturated fatty acids (PUFA), be- of the blood vessel endothelia is transformed cause they are so easily oxidized.25-27 When into its opposite when vitamin E is included the longer-chain PUFA are ingested at high in the experimental design.11-15 Vitamin E was doses, it is unlikely any amount of added anti- found to protect PUFA from their near-spon- oxidants will totally guarantee against rancid- taneous degradation to peroxides and other free ity. Substantial dietary intakes of these highly radical endproducts. These findings are con- reactive fatty acids, without the requisite pro- sistent with the proven clinical protection tection against oxidation, sets the stage for a against vascular morbidity and mortality con- paradoxical toxicity from these nutrients.28,29 ferred by supra-RDA intakes of vitamin E, as Much the same is true for the inges- established from epidemiologic studies.11 tion of oxidized cholesterol derivatives versus Oxidized PUFA and other oxidant pure cholesterol.3 The pure material does not agents also may contribute to endothelial dis- appear to be atherogenic, whereas its oxidized ruption by way of pro-inflammatory factors derivatives are highly toxic to the endothelium that they yield in vivo. One such is TNF, or and correspondingly atherogenic. Cholesterol tumor necrosis factor, which has been detected is relatively resistant to oxidation, but food pro- in human atheromatous plaques and is pro- cessing often accelerates its oxidative break- duced at higher rates in lesioned areas of the down. OxChol derivatives are ubiquitous in vessel wall.18 TNF promotes coagulation and foods coming from animal sources. inflammation, and can directly injure endot- The essential fatty acids (EFAs) are helial cells by way of generating oxygen radi- really vitamins, as judged from the occurrence cals. Exposure to TNF can deplete intracellu- of deficiency states.5,31,32 Two fatty acids that lar antioxidant levels, and also may “fool” the belong to 2 different chemical classes have damaged endothelium into producing “adhe- been proven essential in humans. One is li- sion molecules” on their surfaces. Such mol- noleic acid (LA, C18:2 n-6), of the omega-6 ecules facilitate the attachment of monocytes class; the other is alpha-linolenic acid (ALA, from the circulating blood, thereby increasing C18:3 n-3), of the omega-3 class. Exposure the probability of inflammatory discharges in of cultured endothelial cell sheets to impure close proximity to the vessel wall.6,22 preparations of these EFAs resulted in de- While the findings to date overwhelm- creased barrier function, i.e., albumin or LDL ingly suggest that dietary intakes of oxidized passed across the endothelium more fatty acids and cholesterol (“rancid fats”) are freely.25-27 The extent of endothelial dam- largely responsible for the initiation and pro- age was roughly proportional to the number motion of atherosclerosis, a similarly impres- of double bonds in each fatty acid (FA), and sive body of research indicates that non-oxi- the experimental addition of small amounts of dized forms of essential fatty acids are crucial the peroxides of these FAs markedly increased for endothelial homeostasis and for protection damage to the endothelial cell sheets. Oxi- of the vessel wall against atherosclerotic pro- dized cholesterol derivatives also were devas- gression. tating to the endothelia, even when present in

Platelet Membrane Phospholipids

tty Acid Balance tty Acid

Phospholipases endoperoxides are later Arachidonic Acid converted to prostanoids, Cytosolic Membrane Lipoxygenase Cyclooxygenase either by prostaglandin synthetase to prostaglandins, or by thromboxane synthetase 12 Hydroperoxyeicosatetraenoic Acid PGG2 PGH2 (12 Ð HPETE) to thromboxanes. Thromboxane Each prostanoid is Peroxidase Synthase named for its chemical re- TxA2 lationship to prostanoic 12 Hydroxyeicosatetraenoic Acid (12 Ð HETE) acid. To the applicable PG or Tx is added a third let- FIGURE 3. ter—E, F, A, B, C, or D— denoting functions in the 5- membered ring of pro- Prostanoids and Other stanoic acid. Each prostanoid is also assigned Fatty Acid Metabolites a number subscript that refers to the number The literature on fatty acid metabolites of double bonds in the side chain, and some- and their involvements in homeostasis, inflam- times an alpha or beta is also assigned based mation, and pathology is so massive that this on the configuration of substituents on the ring. section can serve only as a modest orientation The primary PGs in vivo are PGE1, E2, E3, and introduction. F1a, F2a, and F3a. PGE1 was the first prostag- The 20-carbon fatty acids located in landin to be chemically defined, and also the cell membranes can be metabolized to a vari- first to be employed therapeutically (for a re- ety of smaller, messenger-type molecules; this view see Sinzinger et al 20) broad group are the eicosanoids. Within the Prostanoid tissue concentrations usu- eicosanoid group, metabolites of the enzyme ally are very low (on the order of nanomoles, cyclo-oxygenase are termed prostanoids; in- 10-9 molar or less),20,35 yet the prostanoids are cluded in this subgroup are the prostaglandins ubiquitous messenger substances. Among and the thromboxanes. Metabolites of the their many functions, the prostanoids are in- lipoxygenase enzyme are called leukotrienes; volved in the stimulation of smooth muscle these are not prostanoids but are taken together and the dilation and constriction of blood ves- with the peroxide metabolites into the broader sels; in bronchial dilation and constriction; in group of eicosanoids. The prostanoids, rather platelet aggregation; in gastric secretion; in the than the leukotrienes or other eicosanoids, have induction of labor, abortion or menstruation; been most intensely investigated for their ef- and in the regulation of ocular pressure.34-37 fects on the vessel endothelial system. The prostanoids regulate tissue activity on a The first, and rate-limiting, step in second-by-second time scale, as evidenced by prostanoid synthesis is the breaking away of their activity at very low concentrations, their the 2-position fatty acid “tail” from a mem- very short half-lives, and the existence of en- brane phospholipid by the enzyme phospholi- zyme systems specifically responsible for de- pase A2.33 While still in the membrane, the grading them.20 resultant “free” fatty acid is attacked by The most significant precursor of lipoxygenase and other enzymes to eventually prostanoids in human tissues is arachidonic generate leukotrienes; or by cyclooxygenase acid (AA), C20:4 n-6. AA gives rise to the 2- to yield an endoperoxide (see Figure 3). The series prostanoids, which are quantitatively

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 155 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission most abundant in the endothelia as well as all to platelet activity: it is highly pro-thrombotic. the other tissues. AA can be obtained directly In contrast, TxA1 (from DGLA) has little pro- from the diet only by way of animal sources. thrombotic activity, and TxA3 (from EPA) has Plant foods provide precursors of AA, includ- even less. Here the concept of prostanoid bal- ing the shorter chain linoleic acid (LA, C18:2 ance assumes new relevance: atherosclerotic n-6), gamma-linolenic acid (GLA, C18:3 n- progression can be influenced through dietary 6), or dihomo-gamma linolenic acid (DGLA, manipulation of prostanoid balance. C20:3 n-6). In addition to AA, two other 20- Principle number three: prostanoids carbon fatty acids are sources of prostanoids: are generated by way of free radical interme- DGLA yields the 1-series prostanoids, while diates.17 Early along the pathway from the EPA (eicosapentaenoic acid, C20:5 n-3) yields 20-carbon FA to its prostanoid end-products, the 3-series prostanoids. unstable intermediates are generated that have strong free radical character. These include Prostanoid Operating Principles various “lipid peroxides,” including endoper- Prostanoid research is still encumbered oxides and malondialdehyde, which can with unanswered questions and apparent para- crosslink biological macromolecules and cause doxes. Nonetheless, some “operating prin- toxic cell damage. Antioxidant factors that ciples” about prostanoids are evident. down-regulate lipid peroxidation also down- Prostanoid principle number one is that regulate the oxidative prostanoid pathways, prostanoid biochemistry is interwoven, per- steering the outcome towards anti-inflamma- 15-17 haps to the point of being maddeningly laby- tory prostanoids. High oxidative stress rinthine. The many prostanoids, generated and/or low antioxidant defense favors adverse from at least 3 starting sources by several dif- prostanoid balance (pro-inflammatory, perhaps ferent enzyme activities, interfere with each even pro-atherosclerotic). Prostanoid balance other in ways both constructive and destruc- is therefore closely linked to oxidant-antioxi- tive. Prostanoids can inhibit each other by dant balance. competing for the same receptor sites on tar- An adjunct to Prostanoid Principle 3 get cells, or they can act at different receptor is that prostanoid synthesis is tightly integrated sites to either amplify or dampen each other’s with cell membrane systems. Crosslinking of effects.35-39 For this reason alone, any single the membrane lipids due to toxic/free radical research finding on a prostanoid is likely to attack; deficiencies in membrane antioxidant have little predictive value; it must first be as- protection; oxidative damage to the membrane sessed in the context of the large body of data enzymes of the prostanoid pathways; all can about prostanoids that already exists. shift the membrane’s intrinsic balance towards Prostanoid principle number two: the pro-inflammatory or other abnormal 2-series prostanoids (derived from arachidonic prostanoid patterns. Still, anti-inflammatory acid) are more pro-inflammatory (and poten- prostanoid balance is favored only if dietary tially more pro-atherosclerotic) than are those fatty acid intake is appropriately balanced in of the 1- and the 3-series.20,39 The differences favor of GLA-DGLA or ALA-EPA, the “anti- 39 lie mainly in the thromboxanes, the inflammatory” prostanoid precursors. prostanoids that generally stimulate platelets One concrete example of the importance of to aggregate and discharge (these are “pro- antioxidants for prostanoid biology, is that enzymatic synthesis of either of the antithrombotic,” whence comes their name). TxA2 lowers the platelet discharge threshold, thereby inflammatory PGE1 or PGE2 from AA- increasing the risk of vessel wall damage due endoperoxides requires glutathione as a

CELL OUTER MEMBRANE Balance tty Acid

Phosphatidylinositol, phosphatidylcholine Phospholipase A 2 CELL INNER MEMBRANE

Vit. E stabilizes cell membrane 12 - HPETE 12 - HETE & prevents oxidation

Arachidonic Acid Glutathione Peroxidase Selenium

15 - HPETE 15 - HETE

Glutathione Peroxidase Selenium

5 - HPETE 5 - HETE

Glutathione

Leukotriene A4 Leukotriene C4 Cysteinylglycine

Glutathione Leukotriene B4 Leukotriene D4

Glycine PGG2

Leukotriene E4 Glutathione Thromboxane A2 PGH2 Prostacyclin (PGI2) Cysteinylglycine Platelets

Leukotriene F4 Thromboxane B2

PGD2 PGE2 PGF2

FIGURE 4.

cofactor.16,17 With depletion of GSH the ALA, and even the normally innocuous OA prostanoid balance is shifted towards throm- when given alone were toxic to the cells.24-27 boxanes. Vitamin E, the antioxidant most This does not seem to follow the same pattern tested for endothelial protection, also modu- in animal experiments. A plausible explana- lates prostanoid generation towards the tion for this apparent inconsistency is that a prostacyclins.11-15 Both E and glutathione direct exposure to one fatty acid in culture can appear to be major protective antioxidants for crowd out other FAs from the cell membrane, the endothelia 17 (see Figure 4). reducing the viability of the cell. These Prostanoid Principles are likely to be operative not just in the blood vessel en- GLA, DGLA and 1-Series dothelia but in circulating platelets, monocytes, Prostanoids are Protective and other white cells. Prostanoid balance tends In the endothelial cells, as in other cells to respond favorably, i.e., pro-homeostatically, of the body, membrane fatty acid distributions to the appropriate manipulation of dietary fatty are reflective of dietary fatty acid intake.3,10,19 acid intake. One puzzling set of observations The phospholipids are the holding sites for FAs made with endothelial cell cultures is that LA, in the cell membrane: the position 1 tails most

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 157 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission often carry saturates or mono-unsaturates, gation agent, and a bronchodilator. When ad- while AA occurs often in the tails of position ministered directly, PGE1 has anti-inflamma- 2.33,56 Either of the proven-essential fatty ac- tory action, even at very low concentrations -9 -13 37 ids (LA and ALA) can replace each other (or (10 to 10 molar). PGE1 has a spectrum AA or OA) in the membrane phospholipids, of action that differs clearly from the anti-in- depending on their relative dietary intake lev- flammatory actions of PGE2 or PGI2 els.32 Therefore the prostanoid profile of the (prostacyclin), so may have its own, distinc- endothelium (or other particular tissue) at a tive functional niche.35 particular point in time is likely to be an inte- The drawback to administering PGE1 grated outcome of the membrane fatty acid dis- as the native orthomolecule is that, like most tributions within that tissue.5,41 known prostaglandins, its persistence in the In the context of dietary fatty acid in- circulation is very short (half-life on the order takes being the major determinant of endot- of a few minutes). Horrobin suggested that helial prostanoid balance, the question could oral supplementation with GLA-DGLA plant be asked, “What is the anti-atherosclerotic po- oil could be the most practical means to shift tential of gamma-linolenic acid (GLA)?” This the tissue prostanoid balance towards PGE1 FA has been championed as a clinically use- and the other 1-series prostanoids.35,39 Fan, ful dietary supplement by Dr. David Chapkin and their collaborators at Texas A& Horrobin.35,36,39 The first product of dietary M University showed in a series of experi- GLA (C18:3) after its enzymatic elongation ments with mice, that a GLA+omega-3 com- is DGLA (C20:3), which is the immediate pre- bination diet (primrose oil plus fish oil) down- cursor of the 1-series prostanoids. regulated mice macrophages and upregulated 38 GLA is undoubtedly relevant to PGE1 levels in vivo. As discussed in the next prostanoid balance in the human. Horrobin and section, this n-6/n-3 combination has clinical others have shown that dietary supplementa- potential for moderating atherogenic progres- tion with GLA from plant oil sources raises sion in a dose-dependent fashion. the levels of GLA and DGLA in the tissues, and increases the tissue ratio of DGLA/AA.35 Mixed Clinical Findings Levels of DGLA can get as high as one-third From Fish Oils of the AA levels in human tissues, and in some Eicosapentaenoic acid or EPA (C20:5 tissues (adrenal, renal medulla, ovaries, tes- omega-3) is precursor to the 3-series pro- tes) DGLA levels may be equal to or greater stanoids. Over the past two decades, a great than AA: and in almost all human tissues deal of research has been conducted in efforts 35 DGLA levels are 2-4 times higher than EPA. to establish whether EPA and the 3-series Therefore on a quantitative basis, DGLA is a prostanoids are responsible for the low inci- significant prostanoid precursor. In support dence of atherosclerosis in Eskimos and other of a physiologic role for DGLA, Horrobin has fish-eating populations.22 Fish are generally pointed out that low DGLA levels appear to high in EPA, and as a rule these human popu- be strong markers of risk of coronary artery lations consume sufficient fish to have marked 5,35 disease. elevations of EPA in their cell membranes. The PGE1 coming from DGLA is the best fish oil “hypothesis” suggests that, as a con- 35,37 35 studied 1-series prostanoid. Horrobin sequence of high EPA intake, AA is partly dis- has catalogued an impressive range of clinical placed from the cell membranes and the tis- benefits from PGE1, all related to its high po- sue prostanoids shift to a more anti-inflamma- tency as a vasodilator, an anti-platelet aggre- tory, anti-atherogenic pattern due to the

tty Acid Balance tty Acid

prostanoids generated from cell membrane accompanied by rises in LDL cholesterol.52 EPA.22,76 Considering the involvement of Also at high doses (10 grams per day or saturated, monounsaturated, and many poly- higher), the fish oils had adverse effects—in- unsaturated fatty acids in the diet, this asser- creased bleeding time and gastrointestinal side tion may be somewhat simplistic. Yet dietary effects were common, and immune system fish oil supplements unquestionably can ex- competence was threatened. Results from tend the lives of subjects with heart dis- other controlled trials suggest that low doses ease.40,41,50-54 of fish oils can effectively save lives, and with In a randomized, controlled trial minimal adverse effects. Salachas and Saynor reported from Greece that Burr’s group conducted a large ran- 10 grams of fish oil per day relieved angina domized, controlled trial now known as the and reduced subjects’ dependence on glyceryl South Wales Study.53 They found that a mod- trinitrate.40 In a small controlled trial on heart est intake of fatty fish (2 or 3 portions per transplant recipients, conducted by week) significantly reduced the risk of death Fleischhauer and colleagues at Stanford Uni- from heart attack in men who had already had versity, fish oil supplements improved endot- one attack. Siscovick’s group in Seattle sur- helial-dependent coronary artery vasodila- veyed 334 patients who experienced primary tion.50 In a double-blind study by McVeigh cardiac arrest between 1988 and 1994.41 By and collaborators, dietary fish oil improved means of interviews, blood testing, and com- vasodilation capacity in both the large arteries parisons with a control group, they determined and the peripheral vasculature of diabetics.51 that an intake of 5.5 grams of fish omega-3 Concerning the efficacy of the fish oils FA per month (equivalent to one fatty fish meal for directly slowing atherosclerosis, results per week) was associated with a 70 percent have not been as clearcut. To date, some eight reduction in the risk of primary heart attack. controlled trials have examined fish oils for Wallace and colleagues in Northern Ireland the prevention of re-stenosis after gave a similar dose as fish oil (2.4 grams fish angioplasty.42-49 Of these, 5 reported ben- oil, or about 0.7 grams EPA+DHA, per day) efits,42-46 and 3 did not.47-49 One variable that to healthy women in a double-blind trial.54 was inadequately controlled in these clinical They recorded significant anti-inflammatory trials was the antioxidant status of the subjects. effects that were not influenced by the absence Also, Horrobin suggested that had the fish oils of vitamin E from the preparation. Thus the been administered in conjunction with GLA, unfavorable benefit-risk characteristics of the anti-inflammatory clinical benefits might have fish oils at high doses appears to become far been more completely achieved.35,39 Recently more favorable at low doses. he reported success in one trial with a mixture of GLA and fish oils against re-stenosis.5 A Neo-Eicosanoid Pathway to Clinical benefits from the fish oils may Vessel Wall Protection? well depend on dose. When given at high Buchanan and Brister at the McMaster doses the fish oils did not consistently produce Clinic in Ontario, Canada have demonstrated clinical benefit; even at very high doses (up to a pathway for possible vessel wall protection 100 grams per day) they did not consistently that utilizes, rather than the 20-carbon fatty lower LDL cholesterol or raise HDL choles- acids, a linoleic acid (C18:2 n-6) derivative terol. They did consistently lower blood trig- generated by the enzyme lipoxygenase.19 This lyceride levels,30 though this effect was not derivative could be a new messenger on the proven to lower disease risk and at times was

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 159 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission block, different from the archetype 20-carbon- helial cells secrete little of the recognized derived prostanoids and other eicosanoids. antithrombotic factors such as prostacyclin, Platelets are normally geared to re- tissue plasminogen activator, or endothelin. spond to vessel wall injury by secreting These seemingly are produced and released procoagulants, proaggregatory agents, and only following trauma of the wall. Instead, mitogenic factors which homeostatically fa- unstimulated endothelial cells continually pro- cilitate hemostasis and vessel wall repair. duce 13-HODE (13-hydroxy octadecadienoic Under optimal conditions, the platelets circu- acid), from linoleic acid via their 15- late freely with the blood and do not interact lipoxygenase enzyme. 13-HODE confers on with the vessel endothelium. Damage to the the RESTING endothelial cell sheet a marked endothelial sheet, especially if it exposes the resistance to platelet or monocyte adherence, underlying subendothelial layer, often causes apparently by down-regulating adherence re- platelets to become activated. They adhere to ceptors at the surfaces of the endothelial cells. the damaged endothelium and initiate fibrin Dietary EPA (C20:5, n-3) failed to confer this precipitation and clot formation. As with other benefit, though it did decrease platelet of the body’s mechanisms for response to in- adhesivity. jury, the platelets are finely poised—if their Since it is not generated from a 20-C discharge cascade escapes homeostatic con- fatty acid, 13-HODE is not technically a straints it can worsen damage, exaggerate clot prostanoid, though it could qualify as an formation, and threaten to occlude the vessel. eicosanoid, since it is produced by a Antithrombotic strategies are therefore an im- lipoxygenase enzyme. Human arteries make portant facet of atherosclerosis prevention and 6x more 13-HODE than do veins, and its syn- management, and so far these have mainly in- thesis declines with age.55 Buchanan and volved the use of prostanoid blockers i.e., Brinster19 hypothesized that 13-HODE ren- cyclo-oxygenase enzyme inhibitors such as ders the healthy endothelium (and aspirin. subendothelium) relatively resistant to fibrin Buchanan and Brister19 reviewed the clot or platelet thrombus formation. Their pre- mechanisms involved in platelet stimulation, liminary experimental findings indicate dietary discharge, and aggregation. They found that, LA can be beneficial, perhaps to help coun- contrary to the prostanoid dogma, terbalance thromboxanes derived from AA and lipoxygenase metabolites were produced in far so enhance anti-thrombogenic balance in the greater amounts by the platelets than was blood vessel wall. TxA2, (thromboxane A2, a major cyclo-oxygenase metabolite). and such metabolites play Non-Prostanoid Protection a crucial role in normal platelet function. by Dietary Fatty Acids Lipoxygenase activity potentially bypasses Notwithstanding the central impor- conventional antithrombotic management and tance of prostanoids in the prevention or pro- could be pro-thrombotic under conditions of motion of atherosclerosis, dietary long-chain oxidant excess or antioxidant deficiency. For fatty acids (that is, derivatives of n-6 and n-3 example aspirin blocks the cyclo-oxygenase that EFA ranging from C18 to C22 in chain length) generates prostanoids but fails to block the offer benefits to the blood vessel endothelia lipoxygenase, and this could allow for a para- by additional mechanisms that do not directly doxical enhancement of thrombosis by aspirin. involve prostanoids. These include: Buchanan and Brinster claim that un- 1. Moderation of the AA content of der basal, pro-homeostatic conditions, endot- the cell membranes. The unsaturated fatty

Oleic Linoleic Linolenic Balance tty Acid (N - 9) Family (N - 6) Family (N - 3) Family Olive, Cashew, Pecan Corn, Soy, Safflower, Flax, Walnut, Almond, Filbert, Sunflower, Sesame Soy, Green Plants, Macademia, Avocado Pumpkin, Algae

∆6 Desaturase *1 ∆6 Desaturase *1 B6, Mg, Zn, B3, C B6, Mg, Zn, B3, C

Gamma-Linolenic (GLA) Stearidonic Evening Primrose, Black Current, Borage

Elongase B6 C, B3, Zn Dihomo-gamma-linolenic Eicosatetraenic Breast Milk, Spirulina

∆5 Desaturase *2 Zn, B3, C OUTER MEMBRANE

Phosphatidylcholine or other Phospholipid carrier Phospholipase A2 *3 INNER MEMBRANE

PGE1 Series *4 Arachidonic Eicosapentaenoic (EPA) Meat, Milk, Eggs, Shrimp Cold Water Fish, Wild Game

5 - Lipo-oxygenase *55Cyclo-oxygenase - Lipo-oxygenase *5

Leukotrienes PGE2 PGE3 Leukotrienes (LT Series) Series Series 4 Clupanodonic (LT5 Series Adrenic less active than LT4 Series) ∆4 Desaturase

Docosapentanoic Docosahexanoic (DHA) Brown Algae, Cold Water Fish

*1: ∆6 Desaturase inhibited by ETOH, Saturated Fats, Trans- Fats/Hydrogenated Fats, and some chemicals. Caffeine, Diabetes and old age diminish this enzyme’s activity. *2: ∆5 Desaturase may be stimulated by insulin and inhibited by Glucagon and EPA. *3: Phospholipase A2 inhibited by Vit. E, Selenium, Curcumin *4: No Leukotrienes formed in Series 1 pathway *5: 5-Lipo-oxygenase inhibited by Mahonia aquifoliom, Boswellia, Flavonoids from Green Tea, Silymarin, Glycyrrhiza & Quercetin

FIGURE 5.

acids compete with each other (and with the position tails of the phospholipids; at high saturates and omega-9 monounsaturates) for enough intakes other FAs literally can crowd inclusion in the phospholipids that make up AA out of the membrane’s phospholipid the cell membranes. In particular, the various matrix. However, the fact that AA itself is dietary PUFAs compete with AA for the 2- homeostatically conserved in cell membranes

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 161 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission suggests that a range of optimal AA levels may decrease the activity of this enzyme; it is exists.56 An over-substitution of membrane also a major nutrient constituent of fish and AA could interfere with signal transduction, fish oils. DHA is universally present in hu- the carrying of signals into the cell by way of man cells, and in studies with human endot- the membrane (as contrasted with AA helia DHA had several anti-atherogenic ef- prostanoids carrying signals from the mem- fects. DHA down-regulates endothelial cell brane to the environment outside the cell). A surface adhesion receptors—proteins that pro- corollary here, is that overdosing either with mote adhesion of white cells—and so can pro- the fish oils, with GLA, or with linoleic acid, mote atherosclerosis.58-60 DHA also down- is possible and has negative implications for regulates pro-inflammatory mediators, and vessel wall homeostasis. turns off the intracellular reading of the genes 2. Inhibition of AA synthesis from for these substances.61,68 In platelets, DHA its precursors. Here 18-and 20-carbon, down-regulates receptor affinity for thrombox- omega-3 precursor fatty acids compete with anes, inhibiting platelet aggregability.62-64 omega-6 precursor fatty acids for the active These pro-homeostatic DHA effects sites on the elongase and desaturase enzymes. were proven distinct from prostanoid effects. The net outcome should resemble dietary Instead, they reflect DHA’s capacity to increase down-regulation of cell membrane AA (see membrane fluidity and so improve the perfor- Figure 5). mance of proteins built into the membrane. 3. Facilitation of membrane proteins EPA also exhibits these effects, but to a lesser through membrane fluidity.56,57 Transport extent than does DHA, which is consistent with enzymes, ion gates, receptors, and other inte- EPA’s lesser degree of fluidizing capacity. gral membrane proteins all function best when The strategy of optimizing omega-6 to associated with phospholipids carrying fatty omega-3 balance in order to benefit the circu- acids that are highly unsaturated.56 This comes lation may not be as straightforward as used from a direct, intimate association between the to be assumed. As an example, EPA and DHA protein and the highly fluid fatty acid “tails;” peroxide products were found to facilitate the generally, the more unsaturated its fatty acid peroxidation of AA that leads to the genera- tails, the more fluidizing is the phospho- tion of series 2 prostanoids.65 Conversely, lipid.33,56,57 Antigens and membrane-bound peroxidized AA was found to facilitate the antibodies depend on the phospholipid-fatty generation of 3-series prostanoids from EPA. acid matrix. The ATPase transport enzymes These complex metabolic entanglements in- are highly dependent on the lipid matrix for dicate that all the prostanoid precursor fatty functionality, as are the wide variety of recep- acids are homeostatically involved in human tors and the membrane enzymes downstream health and cardiovascular functioning.5,66 of them—adenylate cyclase and protein ki- nases, for example. The most fluidizing of Fatty Acid Diversity, Key to the membrane fatty acids is DHA. Atherosclerosis Prevention Docosahexaenoic acid (DHA, C22:6) Essential fatty acids and their longer- is not a prostanoid precursor, but with 6 double chain derivatives are located at the core of cell bonds it is the most highly polyunsaturated function, the outer membrane system. They 5,57 fatty acid of physiologic significance. are crucial for membrane intregrity through DHA is an omega-3 FA that can be synthe- their phospholipid parent macromolecules, and sized from the essential ALA, though there is they are the primary sources of messenger evidence that age and some disease processes molecules that traverse the membrane in all

tty Acid Balance tty Acid

directions. Metabolic competence to convert The trans-fatty acids are at least as trouble- cell membrane fatty acids to protective some as the saturates.5,69 Monounsaturates prostanoids is one pillar of endothelial homeo- are beneficial, at least to the extent that they stasis. Another pillar is the pro-homeostatic replace saturates. Olive oil or other plant oils benefit from membrane fatty acids by way of high in oleic acid (OA, C18:1) are preferable non-prostanoid pathways. Yet another pillar for frying, since OA is relatively stable to oxi- is the net favorable antioxidant status over dation and does not appear to be toxic to the oxidant challenge. Endothelial functionality endothelia.70 However, Horrobin cautions5 is a net outcome of the dietary intake patterns that extended high intakes of monounsaturates of the 18- and 20-carbon PUFA and their could logically lower membrane EFA and im- longer-chain derivatives,5,66,67 translated into pair homeostasis. metabolites with the intimate participation of ¥ Arachidonic acid intakes from the membrane antioxidants. SAD (Standard American Diet) are likely to The milieu of the cell membrane is be higher than is consistent with pro-homeo- where sophisticated eicosanoid cascades are static, anti-atherosclerotic FA balance. In place initiated. It appears that by way of enzymes of AA from animal sources, LA from plant that interact also with the phospholipid parent sources may offer benefit, perhaps as a source molecules and with antioxidant factors, virtu- of protective 13-HODE and certainly by com- ally all the unsaturated fatty acids in the mem- peting with AA for slots in the cell membrane brane can be metabolized to peroxides, hydro- phospholipids.19 Here again, too much of a peroxides, prostaglandins, thromboxanes, good thing may be possible. AA is central to leukotrienes, and other metabolites still being eicosanoid production and signal transduc- defined. These metabolites interact in com- tion,5,56,57 so an excess of LA intake and/or a plex yin-yang fashion, at times competing and compromise of desaturase activity could lead at other times synergizing with each other to to an excess of membrane LA simultaneous support the blood circulation and help protect with deficiency of DGLA and AA. the vessels against dysfunction or damage.66 ¥ Omega-3 FAs benefit vessel wall ho- Horrobin5,39 has presented convincing meostasis, but not in as simplistic a fashion as evidence that much of the pathophysiology of was earlier hypothesized. Inconsistent clini- atherosclerotic progression—elevated arterial cal results may be related to dose, and lower lipid deposition, intimal hyperplasia, elevated intakes may be just as clinically effective as cholesterol levels, enhanced platelet aggrega- high intakes.40,41 Of the omega-3 FAs, ALA tion, vasoconstriction and increased blood is found in high quantity in flax seed oil, which, pressure, increased plasma fibrinogen—can be though too unsaturated and thus too unstable accounted for more plausibly by deficits of for cooking, makes (subject to personal taste) EFAs than by any other known risk factor. Yet, an attractive salad dressing. In one clinical from the still-murky perspective of membrane trial conducted in France, ALA reduced CHD fatty acid metabolism, a great deal remains to and total mortality, with blood EPA and DHA be understood before dietary intake recom- found to be significantly elevated.76 Yet flax mendations can be accurately developed. seed oil is not an ideal source of omega-3 FA Some of the consistent patterns are: for all individuals: persons with diabetes or ¥ High intakes of longer chain saturates with hypertension, alcoholics, and the aged all (C12 through C16) encourage atherosclerosis, can have impaired desaturase enzyme capacity, since they raise LDL cholesterol levels prob- and perhaps also smokers and persons under ably through crowding out unsaturates.32,69

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 163 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission stress (see Horrobin5,72 for references). For atherosclerosis and coronary heart disease are these individuals direct supplementation with still universal in Western societies. Rational EPA and DHA may be obligatory. nutritional-orthomolecular approaches to ath- The recent positive clinical outcomes erosclerosis prevention are fast becoming from fish oil intakes of 2.4 to 5.5 grams per “mainstream,” due to the overwhelming evi- day (EPA+DHA ≥0.7 grams) are consistent dence that atherosclerosis progression and with a “crucial threshold” for benefit as sug- endothelial functionality are linked to nutri- gested by Odeleye and Watson.71 These lower ent status. Particularly if utilized in conjunc- levels of intake also should lessen the risks of tion with other wholistic protocols, dietary oxidative damage that accompanies high daily essential fatty acids can be used to heal dam- intake. aged blood vessel walls, to halt atherosclerotic ¥ Real progress is being made towards progression, and over the long term to disarm definition of a desirable ratio for n-6:n-3 in- atherosclerosis as a killer disease. takes. The estimated current intake ratios from the SAD range from 10:1 up to 20:1, in contrast with 2:1 to 4:1 at the end of the 19th Cen- tury.5,66 Most experts agree that current n-3 intakes are far too low, and discussions con- tinue towards formal intake recommendations References for some populations.74 In most cells the ra- 1. Navab M, et al. Pathogenesis of atherosclero- tio is in the 3-5:1 region, and this is likely to sis. Am J Cardiol 1995;76:18C-23C. have meaning for cell and tissue homeosta- 2. Schwartz CJ, et al. The pathogenesis of sis.5 atherosclerosis: an overview. Clin Cardiol All these observed patterns indicate 1991;14:1-16. 3. Hennig B, et al. Nutrition, endothelial cell that for consistent nutritional support against metabolism, and atherosclerosis. Crit Revs atherosclerosis, a balanced intake of a variety Food Sci Nutr 1994;34:253-82. of dietary fatty acids is preferable over 4. Davies MG, Hagen P-O. The vascular “megadosing” with any of the omega- 3, 6, or endothelium—a new horizon. Ann Surg 9 fatty acids. Dietary FAs should be gener- 1993;218:593-609. ously augmented with antioxidants, as uncon- 5. Horrobin DF. Abnormal membrane concentra- trolled free radical attack tends to fuel pro-ath- tions of 20 and 22-carbon essential fatty acids: erosclerotic tendencies, while favorable fatty a common link between risk factors and coronary and peripheral vascular disease? acid-antioxidant interactions tend to retard ath- Prostagl Leukotr Ess Fatty Acids erosclerosis initiation and progression. Peri- 1995;53:385-96. odic assays of red blood cell deformability can 6. DeCaterina R, et al. Omega-3 fatty acids and help validate antioxidant protocols, but for an endothelial leukocyte adhesion molecules. overall antioxidant-fatty acid picture, RBC Prostagl Leukotr Ess Fatty Acids membrane fatty acid assays, which are repre- 1995;52:191-5. sentative of tissue fatty acid status,73 should 7. Kidd PM. Natural Antioxidants, First Line of nicely complement the deformability measure- Defense. In: Kidd PM, Huber W. Living with the AIDS Virus (Chapter 6). Albany, ments. CA:PMK;1991:115-42. Despite the advent of the highly-touted 8. Vlassara H. Recent progress on the biologic cholesterol-lowering drugs and the implemen- and clinical significance of advanced tation of invasive angioplasty and bypass sur- glycosylation end products. J Lab Clin Med gery, benefits to the patient have been limited; 1994;124:19-30.

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