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Home , Oxidative stress

SECTION II

Possible Role of Oxidative Stress in the Pathogenesis of Hypertension

ANTONIO CERIELLO, MD dependent production (13). As a result, eNOS may become a per- oxynitrite generator, leading to a dramatic Recently oxidative stress has been proposed as the cause of hypertension. An imbalance in increase in oxidative stress, since per- superoxide and production may account for reduced vasodilation, which in turn can oxynitrite formed by the NO-superoxide favor the development of hypertension. In vitro and in studies support this hypothesis. reaction has additional detrimental effects The supplementation of , particularly in the form of fresh fruit and vegetables, on vascular function by oxidation of cel- reduces blood pressure, supporting a role for free radicals in hypertension. lular and (14). A decrease in NO bioavailability and Diabetes Care 31 (Suppl. 2):S181–S184, 2008 an increase in oxidative stress are present in human hypertension (15). These find- t is estimated that 30% of the adult hypertension have been provocative: ings are based, in general, on increased population may have arterial hyperten- many inconsistencies remain and causal levels of biomarkers of peroxidation I sion (1) and that 30–60% of diabetic relationships have not been established. A and oxidative stress (16–18). Decreased patients have associated hypertension (2). recent hypothesis pointed out the possi- activity (superoxide dis- Hypertension is often associated with ble role of oxidative stress as a key player mutase and ) and reduced levels metabolic abnormalities such as dyslipi- in the pathogenesis of resistance, of reactive species (ROS) scaven- demia, impaired glucose tolerance, insu- ␤-cell dysfunction, and hypertension (9). gers (vitamins E and C and ) lin resistance, and obesity. This is known may also contribute to oxidative stress as the “metabolic syndrome.” A series of OXIDATIVE STRESS AS (16,17,19). Furthermore, L-arginine, a observations has provoked much specu- CAUSE OF HYPERTENSION — Re- NO precursor that augments endotheli- lation and interest in the phenomenon of garding hypertension, endothelial cells um-dependent vasodilation, acutely im- insulin resistance as a common factor un- play a major role in arterial relaxation. Ni- proves -dependent flow- derlying the link between obesity, diabe- tric oxide is the factor released by the en- mediated dilation of the brachial artery in tes, and hypertension (3). Epidemiological dothelium that causes vascular relaxation patients with essential hypertension (20). data linking hyperinsulinemia, obesity, and (10). The half-life of nitric oxide is only a Growing evidence indicates that hypertension seem to be associative rather few seconds, since it is rapidly degraded NADPH-driven generation of ROS and than causal, but this is inconsistent (4). It by the oxygen-derived free super- activation of reduction-oxidation (re- has become increasingly evident that the oxide anion. Superoxide anion is a major dox)-dependent signaling cascades are relationship between insulin, insulin re- determinant of nitric oxide (NO) biosyn- critically and centrally involved in the role sistance, and blood pressure varies ac- thesis and bioavailability and can thus of Ang II-induced hypertension (21). Ang cording to racial group (5). On the other modify endothelial function. It can also II elicits its actions via two distinct recep- hand, chronic and marked hyperinsulin- act as a vasoconstrictor. In addition, nitric tors: the AT1 and Ang II type 2 receptors ism in patients with insulinomas is not oxide synthase (NOS), and in particular (AT2) (22). Although the AT2 receptor is associated with elevated blood pressure the endothelial isoform of NOS (eNOS), is usually expressed at low density in adults, values (6). Although the causal relation- now recognized as an important source of it is upregulated in pathological states ship between insulin and blood pressure superoxide (11,12). The finding that such as vascular injury, salt depletion, is still inconclusive, evidence suggests eNOS can generate superoxide rather , or cardiac hypertrophy (23). that a reduced hepatic insulin clearance than NO in response to atherogenic stim- Pharmacological studies indicate that may contribute to increased insulin levels uli has led to the concept of “NOS uncou- there is crosstalk between AT1 and AT2 in hypertension (7,8). To summarize, pling,” where the activity of the enzyme receptors and stimulation of the AT2 re- current experimental findings linking hy- for NO production is decreased, in asso- ceptor opposes the effect of the AT1. perinsulinemia or insulin resistance to ciation with an increase in NOS- Whereas stimulation of the AT1 receptor ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● leads to cellular growth, angiogenesis, and vasoconstriction, AT2 receptor stim- From the Centre of Excellence in Diabetes and Endocrinology, University Hospital of Coventry and War- wickshire, Warwick Medical School, University of Warwick, Coventry, U.K. ulation causes opposite effects, anti- Address correspondence and reprint requests to Prof. Antonio Ceriello, Warwick Medical School, Clinical proliferation, anti-angiogenesis, and Science Research Institute, Clinical Science Building, University Hospital–Walsgrave Campus, Clifford vasodilation (23). Thus, AT1 and AT2 re- Bridge Rd., Coventry CV2 2DX, U.K. E-mail: [email protected]. ceptors are ideal candidates for maintain- The authors of this article have no relevant duality of interest to declare. This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and ing a proper balance between the Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted vasodilator agent NO and ROS. Recent educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli data demonstrate that Ang II, acting Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson. through the AT1 receptor, stimulates Abbreviations: DASH, Dietary Approaches to Stop Hypertension; ROS, ; RVD, renovascular disease. nonphagocytic NADPH oxidase, causing DOI: 10.2337/dc08-s245 the accumulation of superoxide, hydro- © 2008 by the American Diabetes Association. gen peroxide, and (24).

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S181 Oxidative stress and hypertension

Thus, in pathological states, the stimula- tients with renovascular disease (RVD) and a decrease in , an in tion of the AT1 receptor by increased cir- compared with either patients with essen- vitro marker of , sug- culating or tissue levels of Ang II will tial hypertension and comparable levels gestive of a reduction in oxidative stress produce an inflammatory response. In of blood pressure or healthy normoten- (35). The DASH 2 study has further high- contrast, blockade of the AT1 receptor, sive subjects and suggested that increased lighted the benefit of following the com- which is accompanied by increased circu- oxidative stress might be related to renal bination DASH diet as well as reducing lating Ang II levels, will stimulate the AT2 artery stenosis and activation of Ras. sodium intake. This combination effect receptor and oppose the effect of AT1 re- These authors found a significant positive reduced blood pressure in both hyperten- ceptor activation, a mechanism that ap- correlation between the urinary excretion sive and normotensive patients greater pears to be involved in the beneficial of 8-iso-prostaglandin F2␣ (a reliable than either dietary change alone and, as effects of the angiotensin receptor block- marker of in vivo lipid peroxidation) and with the DASH diet, was most effective in ers (24). These beneficial effects may be renal vein renin ratio (a highly specific the hypertensive subjects (36). A 6- exerted at various levels, as Cipollone et functional test for the detection of renal month primary care intervention, aiming al. (25) demonstrated that the AT1 recep- artery stenosis, renal hypoperfusion, and to increase fruit and vegetable intake to tor antagonist irbesartan decreases in- activation of Ras) (33). Moreover, Minuz five servings a day in hypertensive sub- flammation and inhibits cyclooxygenase et al. (32) found a significant correlation jects, revealed increases in ␣- and ␤-car- ␤ (COX) and prostaglandin (PG)E2- between the reduction in 8-iso- otene, lutein, -crytoxanthin, and dependent synthase (COX-2/mPGES-1) prostaglandin F2␣ excretion after success- vitamin C and decreases in systolic and expression in plaque macrophages, and ful angioplasty in RVD hypertensive diastolic blood pressure (37). A recent this effect may in turn contribute to patients with baseline Ang II ratio and re- diet and lifestyle modification program plaque stabilization by inhibition of met- nal vein renin ratio. All these findings pro- that incorporated the DASH diet in addi- alloproteinase-induced plaque rupture vide additional evidence for a causal link tion to increased fish intake, increased (25). between renin activation and enhanced physical activity, and moderated alcohol Human studies seem to support a role oxidative stress and may suggest that Ang intake has also shown a benefit on blood of oxidative stress in the development of II is a stimulus for oxidant stress in RVD pressure. In this study, treated hyperten- hypertension. In diabetes and obesity, (33). sive subjects on the 4-month diet and life- which are commonly associated with hy- style program had significant reductions pertension, chronic oxidative stress is ANTIOXIDANTS AND THEIR in blood pressure compared with the con- present (26). Conversely, caloric restric- EFFECTS ON OXIDATIVE trol group. However, at the 1-year follow- tion in the obese and fasting in normal STRESS IN HYPERTENSION —If up, the difference in blood pressure was subjects leads to a marked reduction in oxidative stress is indeed a cause or con- no longer significant and effects on mark- ROS generation and other indexes of ox- sequence of hypertension, then reduc- ers of oxidative damage were not assessed idative stress (26,27). Studies using non- tions in oxidative damage may result in a (38). specific markers of oxidative damage have reduction in blood pressure. Antioxidants A number of trials have investigated observed higher superoxide and hydro- are compounds that are able to trap ROS the use of a combination antioxidant sup- gen peroxide production in hypertensive and thus may be capable of reducing ox- plement rather than dietary incorpora- subjects, which returned to levels ob- idative damage and possibly blood tion. However, most of the studies served for control subjects after blood pressure. investigating combination antioxidant pressure reduction (28). A reduction in The Dietary Approaches to Stop Hy- therapy have looked at all-cause or car- and glutathione pertension (DASH) study has examined diovascular mortality, rarely focusing on peroxidase activity have been observed in the effect of a diet rich in fruit and vege- blood pressure as a primary end point. newly diagnosed and untreated hyperten- tables and a combination diet rich in fruits One of the largest studies, undertaken by sive subjects, compared with control sub- and vegetables, low-fat dairy, reduced fat, the Heart Protection Collaborative Group jects, with superoxide dismutase activity and increased and fiber intake (39), saw no improvement in blood pres- being inversely correlated with blood (34). The fruit and vegetable diet and the sure after treatment with an ascorbic acid, pressure within the hypertensive group, combination diet both reduced clinical synthetic , and ␤- com- but not the control group (29). Higher and ambulatory blood pressure in hyper- bination versus placebo after 5 years in production of has also tensive and normotensive subjects more subjects thought to be at high risk of car- been observed in treated and untreated so than a control diet. The combination diovascular disease. Furthermore, a meta- hypertensive subjects compared with diet was most effective and hypertensive analysis has revealed no clear benefit after normotensive subjects, with a significant subjects showed the greatest benefit. The antioxidant supplementation in either all- correlation between hydrogen peroxide reductions in blood pressure were not cause or cardiovascular mortality (40). levels and systolic blood pressure (30). In due to reduced sodium, BMI, or alcohol, The use of a combination supplement addition, both malignant and nonmalig- which did not change during the study for (zinc, ascorbic acid, ␣-tocopherol, and nant hypertensive subjects had higher any group. In addition, blood pressure re- ␤-carotene) versus placebo has been in- lipid hydroperoxide production, as mea- ductions began in the second week of in- vestigated in both treated hypertensive sured by the ferrous oxidation–xylenol tervention and continued for the 6-week and normotensive subjects. The combi- (FOX) assay, compared with control sub- duration of the study, reaching targets ob- nation supplement resulted in a signifi- jects (31). served after drug therapy (34). A sub- cant reduction in systolic blood pressure Accordingly, Minuz et al. (32) re- study using the DASH diet demonstrated in both hypertensive and normotensive cently demonstrated that oxidant stress is that this modification in diet resulted in groups versus placebo and a nonsignifi- markedly increased in hypertensive pa- an increase in serum antioxidant capacity cant reduction in diastolic blood pres-

S182 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Ceriello sure. Markers of oxidative damage were possibility that its reversal can add ef- Briscoe P, Ku D, Bradley WA, Gianturco not measured, although levels of circulat- fective advantages in antihypertensive SH, Gore J, Freeman BA, et al.: Superox- ing vitamins increased (41). treatment. ide and peroxynitrite in . These data are consistent with the ev- Proc Natl Acad SciUSA91:1044–1048, idence that several antioxidants, particu- 1994 References 15. Touyz RM: Reactive oxygen species, vas- larly glutathione and vitamin C, have cular oxidative stress, and signaling shown a blood pressure–lowering effect 1. Haber H: Hypertension: where do we go from here? Hypertension 7:311–312, 1985 in hypertension: what is the clinical in both normal and hypertensive subjects, 2. Drury PL: Diabetes and arterial hyperten- significance? Hypertension 44:248–252, with or without diabetes (42,43). sion. 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