DOI: 10.1515/folmed-2016-0039 REVIEW Pathophysiological Role of , and Asymmetric Dimethylarginine in the Process of Atherosclerosis Daniela Iv. Koleva1,2, Maria M. Orbetzova1,2, Julia G. Nikolova3, Tanya I. Deneva4,5 1 Section of Endocrinology, Second Department of Internal Diseases, Faculty of Medicine, Medical University of Plovdiv, Plovdiv, Bulgaria 2 Clinic of Endocrinology, St. George University Hospital, Plovdiv, Bulgaria 3 Department of Physiology, Faculty of Medicine, Medical University of Plovdiv, Plovdiv, Bulgaria 4 Department of Clinical Laboratory, Faculty of Pharmacy, Medical University of Plovdiv, Plovdiv, Bulgaria 5 Clinical Laboratory, St. George University Hospital, Plovdiv, Bulgaria

Correspondence: Adipose tissue is recognized as a rich source of proinfl ammatory mediators that may Daniela Iv. Koleva, Section of directly contribute to vascular injury, resistance, and atherogenesis. Many Endocrinology, Second De- studies have shown that adiponectin has antiatherogenic and anti-infl ammatory partment of Internal Diseases, properties. Adiponectin acts not only as a factor increasing insulin sensitivity, and Faculty of Medicine, Medical the protective eff ect may result from its ability to suppress production of proinfl am- University of Plovdiv,15A Vassil Aprilov St., 4002 Plovdiv, matory . It negatively regulates the expression of TNF-alpha and C-reac- Bulgaria tive protein (CRP) in adipose tissue; reduces expression of vascular and intracellular E-mail: [email protected] adhesion molecules (VCAM-1, ICAM-1), E-selectin, interleukin-8 (IL-8). Hyperlepti- Tel: +359 898 664 113 nemia has been linked with the development of hypertension and endothelial dys- function/atherosclerosis, two main pathophysiological conditions associated with Received: 21 July 2015 Accepted: 07 June 2016 cardiovascular disease development. Leptin-mediated increases in sympathetic Published Online: 12 Oct 2016 nervous system activity may be among the principal mechanisms evoking obesity Published: 23 Dec 2016 related hypertension. Leptin stimulates the secretion of proinfl ammatory cytokines, and increases the release of -1 (ET-1), which may promote hypertension. Key words: adiponectin, leptin, asymmetric dimethylarginine, Increased serum levels of asymmetric dimethylarginine (ADMA), a physiological endothelial dysfunction, adi- regulator of the biosynthesis of nitric oxide (NO), promote the process of athero- pose tissue sclerosis, leading to the occurrence of endothelial dysfunction and cardiovascular disease. Citation: Koleva DI, Orbetzova MM, Nikolova JG, Deneva TI. Pathophysiological role of adiponectin, leptin and asy- mmetric dimethylarginine in the process of atherosclerosis. Folia Medica 2016;58(4):234-240 doi: 10.1515/folmed-2016-0039

INTRODUCTION being the endothelial dysfunction. ED accompanied Recent insights into the basic mechanisms involved by infl ammation in the vessel wall is characterized in atherogenesis indicate that deleterious altera- by increased lipoprotein oxidation, smooth muscle tions of endothelial physiology, also referred to as cell proliferation, extracellular matrix deposition, endothelial dysfunction, represent a key early step accumulation of lipid-rich material, activation of in the development of atherosclerosis and are also platelets, and thrombus formation.2 involved in plaque progression and the occurrence Adipose tissue is no longer viewed as a passive of atherosclerotic complications.1 repository for triacylglycerol storage and a source One of the major risk factor for cardiovascu- of free fatty acids (FFAs). Mature adipocytes are lar disease is the metabolic syndrome (MS). Its widely acknowledged as an active endocrine and components: dyslipidemia, hypertension, insulin paracrine organ secreting an ever-increasing number resistance and abdominal obesity are linked with an of mediators that participate in diverse metabolic pro- infl ammatory and a prothrombotic state. This could cesses.3 More recently, adipose tissue is recognized generate the cardiovascular disease, the fi rst changes as a rich source of proinfl ammatory mediators that

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Adiponectin negatively regulates the expression of TNF-alpha and CRP in adipose tissue. On the contrary, its expression is negatively regulated by TNF-alpha and IL-6. Adiponectin reduces expres- sion of vascular and intracellular adhesion mol- ecules (VCAM-1, ICAM-1), E-selectin, IL-8, and monocyte adhesion to human aortal endothelial cells after their stimulation with TNF-alpha.7 The proliferation and migration of smooth muscle cells induced by platelet-derived growth factor (PDGF) is abolished or diminished by adiponectin action as inhibition of activation of nuclear factor kappa B in endothelial cells. This effect is partially medi- ated by its ability to support the action of cyclic adenosine monophosphate - proteinkinase A system (cAMP-PKA). In endothelial cells, adiponectin inhibits the pro- duction of reactive oxygen species (ROS) induced by high levels of glucose via the above mentioned cAMP-PKA system. Adiponectin inhibits macro- phage transformation to foam cells and reduces the intracellular content of cholesterol esters via sup- pression of expression of scavenger receptors, class ET-1 - endothelin-1; ATII - angiotensin II; oxLDL - oxidized low-density lipoproteins; MCP-1 - monocyte chemoattractant A (SR-A). In these cells, adiponectin reduces lipo- protein 1; SMC - smooth muscle cell; MMP - matrix metal- polysaccharides stimulated TNF-alpha production. loproteinase; EC - endothelial cell. In some recent studies, adiponectin has a posi- tive effect in endothelial homeostasis. It acts as a Figure 1. Anti- and proinfl ammatory adipokines in the process of atherogenesis (adapted from Lau DC et al.28). regulator of the enzyme endothelial nitric oxide synthase (eNOS), which is a key determinant of endothelial function and angiogenesis (the produc- may directly contribute to vascular injury, insulin tion of NO inhibits the infl ammatory response in resistance, and atherogenesis. These proinfl ammatory the arteries), and also promotes phosphorylation of adipocytokines, or adipokines, include TNF-alpha, eNOS in endothelial cells, increases its expression IL-6, leptin, plasminogen activator inhibitor-1 (PAI- and induces NO production after suppression of its 1), angiotensinogen, and C-reactive protein activity caused by the effect of oxidized low-density (CRP) (Fig. 1). On the other hand, nitric oxide lipoproteins (oxLDL).8 (NO)4 and adiponectin confer protection against There is an increasing number of papers on infl ammation and obesity-linked insulin resistance5. experimental models that point to the fact that adiponectin plays an important protective role in ADIPONECTIN AND ENDOTHELIAL DYSFUNC- the development of insulin resistance and diabetes. TION Severe insulin resistance was seen in adiponectin- Adiponectin is an adipose tissue-derived defi cient knockout mice (KOAD) after administration which has protective role in the initiation and progres- of high fat and/or carbohydrates diets. Administra- sion of atherosclerosis through its anti-infl ammatory tion of adiponectin led to reduced hyperglycemia in and anti-atherogenic effects. Adiponectin serum the diabetic mice without affecting insulin levels. levels are decreased in obesity, type 2 diabetes, In another study, increased muscle fatty acid oxi- patients with coronary artery disease, etc.6 The dation and reduction of plasma glucose, free fatty level of circulating adiponectin correlates positively acids and triglycerides were observed. Studies on with high-density lipoprotein (HDL) cholesterol, experimental animal models have revealed that and negatively with infl ammatory markers, markers the administration of adiponectin has a benefi cial of insulin resistance, triglyceride-rich lipoprotein action against the development of obesity and particles, and other adipokines. atherosclerosis. It seems that adiponectin acts not

Folia Medica I 2016 I Vol. 58 I No. 4 235 D. Koleva et al only as a factor increasing insulin sensitivity, and LEPTIN AND ENDOTHELIAL DYSFUNCTION the protective effect may result from its ability to Leptin was one of the fi rst proteins discovered to 7 suppress production of proinfl ammatory cytokines. be secreted from adipose tissue, by the identifi ca- In vitro experiments revealed the physiological tion and sequencing of the ob from the ob/ concentrations of adiponectin inhibited TNF-alpha ob mouse. Daily injection of the in ob/ob induced expression of VCAM-1 and ICAM-1 on mice resulted in a rapid reduction in food intake, the endothelium and exhibited other antiatherogenic body mass and percentage body fat but maintained effects. In 2008, Vaverková et al. published a study lean muscle mass, increased energy expenditure and investigating the relationship between adiponec- restored euglycaemia and reproductive function, tin and serum concentrations of soluble adhesive confi rming that it has an important role in energy molecules VCAM-1 and ICAM-1 as well as with homoeostasis and storage. However, leptin levels markers of insulin resistance and infl ammation in were found to be increased in obese subjects, with patients with cardiovascular disease (CVD) and in little or no impact to regulate energy homoeostasis, 9 dyslipidemic patients at high risk of CVD. The which coined the well-established phrase ‘leptin authors found signifi cant independent positive as- resistance’ in obesity.12 sociation of adiponectin with VCAM-1 but not with Leptin has been implicated in various patho- ICAM-1 serum concentrations in patients with or at physiological mechanisms for CVD development. risk for CVD. Their expression results in adhesion of circulating leukocytes to the endothelial cells and their subsequent transendothelial migration - an important step in initiation and progression of ath- erosclerosis.VCAM-1 and ICAM-1 have a different expression pattern and probably different roles in atherogenesis.10 Soluble forms of these molecules can be measured in peripheral circulation. The origins of circulating soluble cell adhesion molecules are not entirely clear, but they may derive from shed- ding or proteolytic cleavage from endothelial cell. Many studies, including experiments in vitro, animal models and studies in human, have shown that adiponectin has antiatherogenic and anti-in- fl ammatory properties. Low adiponectin levels were found in patients with coronary artery disease (CAD) independently of other risk factors. Therefore, the fi nding of positive and independent association of adiponectin with the marker of endothelial dysfunc- tion VCAM-1 was surprising. This positive asso- ciation was present both in patients with CVD and dyslipidemic subjects without CVD, but it was not signifi cant in healthy subjects without dyslipidemia. The authors hypothesize that adiponectin, which Figure 2. Mechanisms associated with hyperleptinemia accumulates in the arterial wall only in place of and considered to be possible links between obesity and endothelial injury and atherosclerotic plaques (that CVD (adapted from Esler M et al.29). is the same places where VCAM-1 is expressed) may be involved in shedding of ectodomains of VCAM-1 from endothelial surface. This may rep- Hyperleptinemia has been linked with the develop- resent a mechanism by which VCAM-1 effects ment of hypertension and ED/atherosclerosis13,14, on the cell surface can be downregulated. In this two main pathophysiological conditions associated way, adiponectin could protect vascular wall from with CVD development (Fig. 2). adhesion of leukocytes and thus from progression of atherosclerosis.11

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MECHANISMS OF ED/ATHEROSCLEROSIS IN A LEPTIN AND OXIDATIVE STRESS STATE OF HYPERLEPTINEMIA ROS production is enhanced in obesity. Leptin in- duces oxidative stress in human endothelial cells and HYPERLEPTINEMIA ACTIVATES THE SYMPATHETIC NERVOUS mitochondrial superoxide anion production in aortic SYSTEM (SNS) AND/OR ET-1 endothelial cells via augmented fatty acid oxidation. It has been demonstrated that experimental hyper- Excess superoxide production may quench NO, thus leptinemia acutely increases vasoconstrictory sym- favoring the formation of ONOO-, which reduces pathetic nerve activity in healthy humans. Leptin local NO bioavailability.19 This may result in the binds to its receptors in various regions of the central attenuation of dilator responses to NO-mediated nervous system (CNS) - including the hypothalamus agonists, such as acetylcholine (Ach). - activating neural pathways, decreasing appetite, and increasing SNS activity and energy expenditure. HYPERLEPTINEMIA MAY INCREASE VASCULAR TONE AND SNS activation by leptin may occur through both IMPAIR VASODILATATION local peripheral actions and centrally mediated ef- The results regarding the overall effect of leptin fects on the hypothalamus - although intact leptin on blood pressure have been controversial. It is receptors (LRs) and CNS signaling are still required likely that, with only short exposures, the leptin- for this response.15 Leptin-mediated increases in SNS mediated increase in SNS activity may not be suf- activity may be among the principal mechanisms fi cient to cause marked peripheral evoking obesity-related hypertension. and to acutely raise blood pressure. Additionally, ET-1 is a 21-amino acid peptide that is mainly impaired leptin-induced NO production might be produced by the vascular endothelium through the compensated by endothelium-derived hyperpolar- actions of an endothelin-converting enzyme on the izing factor (EDHF). However, chronic increases endothelial cell membrane. ET-1 causes prolonged in plasma leptin, comparable to those found in smooth muscle-mediated vasoconstriction and hy- severe obesity, can raise blood pressure. This effect pertension, affects cardiac stimulation in a manner is partly because the contribution of EDHF to the that can indirectly modify cardiovascular function, hemodynamic effect of leptin becomes ineffi cient, stimulates aldosterone secretion, decreases renal as well as partly due to the activation of leptin- blood fl ow and glomerular fi ltration rate, and releases induced renal mechanisms.20 In fact, some studies atrial . Because of its powerful have demonstrated that long-term leptin administra- vasoconstrictor properties and its effects on intra- tion increases both renal sympathetic nerve activity cellular calcium, ET-1 has been implicated in the and blood pressure, promoting sodium retention pathogenesis of hypertension, coronary vasospasm, and decreasing natriuresis.21 However, in lean rats, and heart failure. Leptin has been shown to induce leptin-mediated increase of renal sodium excre- ET-1 in endothelial cells in vitro, and stimulates tion was not followed by blood pressure changes. ET-1 activity in lean subjects in vivo.16 It has been proposed that the lack of effect after acute leptin administration in vivo is related to LEPTIN AND INFLAMMATION the concept of selective leptin resistance and the Several reports have also demonstrated that leptin “counterbalance theory”. According to this theory, possesses proinfl ammatory -like properties. under normal physiological conditions in vivo, the It has been demonstrated that high plasma leptin simultaneous vasodilatory and vasopressor effects levels up-regulate the expression of monocyte cyto- of leptin counteract each other, making leptin’s 17 kines such as TNF-alpha and IL-6. Leptin levels net hemodynamic effect neutral.22 However, in are also correlated with CRP in both lean and obese obese hyperleptinemic individuals or subjects with subjects. Furthermore, CRP can impact atheroscle- previous endothelial damage, this balance could rosis development by hampering endothelial NO be disrupted. In such cases, hyperleptinemia may production - either directly by decreasing endothelial alter vasodilatation capacity and raise blood pres- NO expression, or indirectly by increasing ROS sure through SNS activation15 and proinfl ammatory production and thus inactivating NO. Leptin may effects17, along with co-existing impairment of NO regulate CRP production in the liver both through synthesis or NO activity. Following this reason- 18 its effects on IL-6 and by direct regulation. ing, the acute effects of leptin would include both

Folia Medica I 2016 I Vol. 58 I No. 4 237 D. Koleva et al vasodilator effects together with SNS stimulation, μmol/l, respectively, p>0.05) as compared to those resulting in an overall neutral effect. in the healthy women (0.65±0.35 μmol/l, p<0.05). Leptin has also been associated with hypertension No signifi cant correlations between ADMA and age, via other mechanisms; for example, leptin increases body mass index (BMI), waist circumference, fasting ROS generation in endothelial cells, which decreases plasma glucose, fasting immunoreactive insulin (IRI), the amount of bioactive NO. As mentioned earlier, homeostasis model assessment of insulin resistance leptin stimulates the secretion of proinfl amma- (HOMA-IR), lipid parameters and systolic blood tory cytokines such as TNF-alpha and IL-6, and pressure in the women with both MS and PCOS increases the release of ET-1, which may promote were found. In women with MS unlike those with hypertension. Interestingly, one study demonstrated PCOS, the diastolic blood pressure showed a sig- a reduction in serum leptin levels with the use of nifi cant negative correlation with ADMA.27 angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), sug- CONCLUSION gesting a potential interaction between leptin and Certain adipocytokines, such as leptin, TNF-alpha the ROS for hemodynamic regulation in obesity.21 and adiponectin signifi cantly affect obesity-related metabolic diseases by controlling fat metabolism, ADMA AND ENDOTHELIAL DYSFUNCTION energy homeostasis, and insulin sensitivity. Indepen- Endothelial dysfunction, a systemic disorder and an dent of their effects on glucose and fat metabolism, early pivotal event in the pathogenesis of atheroscle- some adipokines have been regarded recently as direct rosis, is characterized by reduced production of nitric links between obesity and atherosclerosis because of oxide (NO) and an imbalance between endothelium- their infl uence on the function of endothelial cells dependent vasodilatation and vasoconstriction as well (the production of NO), arterial smooth muscle cells, as antithrombotic and prothrombotic factors. NO and macrophages in vessel walls. The interactions maintains the vasodilatory property of endothelium between the adipose tissue, the vascular wall, and and opposes the effects of such vasoconstrictors the immune system are complex, and these are the like ET-1 and angiotensin II (ANG II). It inhibits key players from which we have to understand leukocyte and platelet activation and aggregation the mechanisms implicated in the development of and, together with prostacyclins, helps to maintain atherosclerosis. In light of recent developments, the endothelium as a smooth nonthrombotic barrier.23 interventions to decrease infl ammation associated The asymmetric dimethylarginine (ADMA), a with metabolic syndrome are actually developed by-product of cellular protein turnover, serves as a and hopefully might in the near future be of great physiological regulator of the biosynthesis of NO benefi t in decreasing the ‘danger’ associated with and is believed to be an endogenous competitive our modern lifestyle. inhibitor of eNOS. It is proved that increased serum levels of ADMA promote the process of atheroscle- REFERENCES rosis, leading to the occurrence of ED and CVD.24 1. Bonetti P, Lerman L, Lerman A. Endothelial dys- Elevated plasma levels of ADMA were demonstrated function - a marker of atherosclerotic risk. Arterio- in patients with diabetes, hypercholesterolemia, scler Thromb Vasc Biol 2003;23:168-75. hypertriglyceridemia, hypertension, preeclampsia, 2. Vincent MA, Montagnani M, Quon MJ. Molecular peripheral vascular disease, congestive heart failure, and physiologic actions of insulin related to produc- acute coronary syndrome.25,26 ADMA is perceived tion of nitric oxide in vascular endothelium. Curr as a marker of ED, a candidate for a new cardio- Diab Rep 2003;3:279-88. vascular risk factor or an independent risk factor 3. Ferroni P, Basili S, Falco A, et al. Infl ammation, for cardiovascular morbidity and mortality. insulin resistance and obesity. Curr Atheroscler Rep In a study of our clinic, which included 24 2004;6:424-31. women with MS, 38 women with polycystic ovary 4. Yan H, Aziz E, Shillabeer G, et al. Nitric oxide syndrome (PCOS) and 24 age-matched clinically promotes differentiation of rat white adipocytes in healthy women, we found significantly higher culture. J Lipid Res 2002;43:2123-9. 5. Kubota N, Terauchi Y, Yamauchi T, et al. Disruption plasma levels of ADMA in both the women with of adiponectin causes insulin resistance and neointi- PCOS and MS (0.91±0.32 μmol/l, and 0.82±0.37 mal formation. J Biol Chem 2002;277(29):25863-6.

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Патофизиологическая роль адипонектина, лептина и ассиметричного диметиларгинина в процессе атеросклероза Даниела Ив. Колева1,2, Мария М. Орбецова1,2, Юлия Г. Николова3, Таня И. Денева4,5 1 Секция эндокринологии, второго отдела внутренних болезней, Факультет медицины, Медицинский университет Плов- див, Пловдив, Болгария 2 Клиника эндокринологии, Университетская больница «Св. Георги», Пловдив, Болгария 3 Кафедра физиологии, Факультет медицины, Медицинский университет Пловдив, Болгария 4 Кафедра клинической лаборатории, Факультет фармации, Медицинский университет Пловдив, Болгария 5 Клиническая лаборатория, Университетская больница «Св. Георги», Пловдив, Болгария

Адрес для кореспонденции: В свете современных данных доказано, что жировая ткань (ЖТ) представляет Даниела Ив. Колева, Секция собой богатый источник проинфламаторных медиаторов, которые непосред- эндокринологии, второго ственно могут привести к поражению сосудов, развитию инсулинорезис- отдела внутренних болезней, тентности и атерогенезу. Рядом исследований установлено, что адипонектин Факультет медицины, обладает антиатерогенными и противовоспалительными свойствами. Адипо- Медицинский университет - Пловдив, бул. Васила Априлова нектин действует в роли фактора, повышающего инсулиновую чувствитель- № 15A, Пловдив, 4002, Болгария ность и характеризуется наличием протективного эффекта, обусловленного E-mail: [email protected] его способностью подавлять производство проинфламаторных цитокинов. Тел.: +359 898 664 113 Он супрессирует экспрессию генов на производство туморнекротизирующе- го фактора альфа (TNF-α) и С-реактивного протеина (CRP) в жировой ткани; Дата получения: 21 июля 2015 г. Дата приемки: 07 июня 2016 г. понижает экспрессию на производство молекул адгезии сосудистого эндоте- Дата онлайн публикации: 12 лия 1 типа и молекул межклеточной адгезии 1 типа (VCAM1, ICAM1), Е-селекти- октября 2016 г. на, интерлейкина-8 (IL-8). Гиперлептинемия является состоянием, связанным Дата публикации: 23 декабря с наличием гипертонии и эндотелиальной дисфункции (ЭД)/атеросклероза 2016 г. – двух ключевых факторов в развитии сердечно-сосудистых заболеваний Ключевые слова: адипонектин, (ССЗ). Обусловленную лептином повышенную активность симпатической лептин, ассиметричный нервной системы (СНС) можно считать основным механизмом, провоциру- диметиларгинин, ющим развитие гипертонии, связанной с ожирением. Лептин стимулирует эндотелиальная дисфункция, секрецию проинфламаторных цитокинов и увеличивает выделение эндоте- жировая ткань лина 1 (ЭД-1), ведущих к развитию гипертонии. Увеличенные сывороточные Образец цитирования: Koleva уровни ассиметричного диметиларгинина (АДМА) – патофизиологического DI, Orbetzova MM, Nikolova JG, регулятора в биосинтезе оксида азота (NO), ускоряют процесс атеросклероза, Deneva TI. Pathophysiological проявляющегося наличием эндотелиальной дисфункции и ССЗ. role of adiponectin, leptin and asymmetric dimethylarginine in the process of atherosclerosis. Folia Medica 2016;58(4):234-240 doi: 10.1515/folmed-2016-0039

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