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Protein & Peptide Letters, 2014, 21, 2-9
The Role of Apelins in the Physiology of the Heart Suna Aydin1, Mehmet Nesimi Eren2, brahim Sahin3,4 and Suleyman Aydin4,* 1
Department of Cardiovascular Surgery, Elazig Research and Training Hospital, Elazig 23200, Turkey; 2Department of Cardiovascular Surgery, Medical School, Dicle University, Diyarbakir 21280, Turkey;3Department of Histology and Embryology, Medical School, Erzincan University, Erzincan 24030, Turkey; 4Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, Elazig 23119, Turkey Abstract: Apelins are a peptide hormone known as the ligand for the G protein-coupled APJ receptor. There are many different forms of apelin in the circulation. Apelins and their receptors are expressed in the central nervous system, including the hypothalamus, and in numerous other peripheral tissues. These peptides are also synthesized in and secreted from the adipose tissues. Additionally, apelins were immunohistochemically shown to be synthesized in smooth muscle cells in the media of the left internal mammary artery (LIMA) and the saphenous vein, fibroblast cells in the media of the aorta and endothelial cells of the intima. Similarly, it was recently reported that the enzyme linked immunoassay (ELISA) measurements of apelins were similar to its immunohistochemical data in the tissues of the aorta and left internal mammary artery. Apelins which are rapidly eliminated from the circulation have a half life of less than eight minutes. The normal concentration of apelins in the human plasma ranges between 1.3 ng/mL and 246±0.045 ng/mL. Apelins serve important functions in food intake, vasopressin (anti-diuretic hormone: ADH) and histamine release, gastric acid, bicarbonate secretion and insulin secretion, diuresis, cell proliferation, angiogenesis, glucose-fluid balance and regulation of gastrointestinal motility and cardiovascular system. Therefore, this review aims to focus on the potential role of the apelin system in the balance of the cardiovascular system.
Keywords: Apelins, cardiovascular system, fluid homeostasis, peptides. INTRODUCTION The cardiovascular system is a closed network system of the heart which pumps the blood from the venous system to the arterial system and blood vessels by way of which the blood circulates the body . The pyramid-shaped heart, measuring 12 cm in length and 9 cm in width, is a hollow, muscular organ located at the center of the thorax. Weighing about 280 to 340 g in males and 230 to 280 g in females, this organ serves the purposes of transferring oxygen, hormones, regulator molecules and nutrients to body cells and carrying away metabolic waste. An average person pumps about 300 million liters of blood in his lifetime . While the heart is at the center of the cardiovascular system (circulation), the blood is delivered to the body by blood vessels . Blood vessels include arteries, arterioles, capillaries, venules and veins . These blood vessels serve significant functions in the adjustment of the amount of blood to be delivered to the organs and regulation of blood pressure. The expanding of vessels is called vasodilation and their compression (shrinking) is called vasoconstriction . Vasodilative (like salusins) and vasoconstrictive/vasodilative (for instance apelins) peptides synthesized in the blood vessels fulfill important functions in the regulation of blood pressure [5-7]. Vasodilation of resistance vessels when *Address correspondence to this author at the Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey; Tel: 90 5334934643; Fax: 90 - 424 - 237 91 38; E-mail: [email protected]
infused into the human forearm , both responses mediated primarily by nitric oxide (NO). In vitro, apelin causes vasodilation of human splanchnic artery, largely depends NO mechanism . Apelin also causes vasoconstriction of human saphenous vein  and mammary artery  in vitro by a direct action on vascular smooth muscle. The scope of this review is to present the past, present and future of apelins which usually exercise vasoconstrictive effects on the cardiovascular system in the light of contemporary data. APELINS Apelin, an adipokinin, was discovered in 1998 by Tatemoto and colleagues in the stomach tissue . In addition to the stomach, apelins are also synthesized in a variety of tissues including the heart, lungs, kidneys, liver, adipose tissue, gastrointestinal system, brain, adrenal gland and endothelium [13,14]. The wide distribution of apelin implies that it has a wide spectrum of activity in different organs. Furthermore, the mRNA of apelin and angiotensin-like 1 receptor (APJ) was detected in almost all organs . The distribution of apelin and APJ receptor resembles that of angiotensin II and angiotensin II type 1 receptors. Besides, although these receptors are structurally similar, their binding receptors are different. The gene of a receptor similar to the angiotensin 1 receptor was found in 1992. Since there was no known ligand in this context, this new receptor was called APJ receptor (angiotension-like 1 receptor). The APJ receptor which is a member of the 377 amino acids 7 transmembrane domain protein groups contains a G-coupled re© 2014 Bentham Science Publishers
The Role of Apelins in the Physiology of the Heart
Protein & Peptide Letters, 2014, Vol. 21, No. 1
36 is the major isoform present in colostrum . Rat brain was found to contain both (Pyr1) apelin-13 and apelin-17 . Apelin synthesis follows the rules of the well-known protein synthesis. The N-terminal edge of apelin contains a signal peptide fragment. Since the sequencing of the 13 amino acids in the structure of apelin is the same in all apelin forms, the basic apelin structure is called apelin-13 . When apelin is transferred to the endoplasmic reticulum, the signal peptide is separated, which leaves 55 amino acids. Of this, some active fragments produce the forms including the 36 amino acids fragment corresponding to 42-77 sequencing (apelin-36), the 17 aa-peptide corresponding to the 61-77 sequencing (apelin-17) and the 13 amino acid-peptide corresponding to 65-77 sequencing (apelin-13) . However, the biological activity of apelins is determined by the N-termino-
ceptor gene on the long arm of chromosome 11. The discovery of the APJ receptor led to the discovery of apelin , as apelin exercises its juxtacrine, paracrine and autocrine, etc. physiological effects through the APJ pathway . Biosynthesis and Structures There is a variety of apelins depending on the number of amino acids (aa) (Table 1). The human apelin gene, localized on chromosome Xq25-q26.1, encodes a 77 amino acid prepropeptide precursor (preproapelin) . The human, bovine and rat preproapelin peptides have a fully conserved sequence in the last 23 C-terminal amino acids, between Trp55 to Phe-77. The predominant isoforms in plasma are (Pyr1) apelin-13, apelin-13 and apelin-17 [16-18], whereas apelin-
Apelin isoforms derived from a 77-aa precursor, preproapelin and their molecular weights.
H2N M COOH NF LP RM LP CG VK QH AS LL LR LP LR WQ LR SR LF TK AR VR CG GG GQ SW LP MG PP LG PN DR GS NG GR LP EQ DV GL N-V-R-H
Functional apelin isoforms
H2N L V Q P R G S R N G P G P W Q G G R R K F R R Q R P R L S H K G P M P F COOH
H2N G S R N G P G P W Q G G R R K F R R Q R P R L S H K G P M P F COOH
H2N N G P G P W Q G G R R K F R R Q R P R L S H K G P M P F COOH
H2N R R K F R R Q R P R L S H K G P M P F COOH
H2N K F R R Q R P R L S H K G P M P F COOH
H2N F R R Q R P R L S H K G P M P F COOH
H2N R R Q R P R L S H K G P M P F COOH
H 2N Q R P R L S H K G P M P F COOH
H2N R P R L S H K G P M P F COOH
N: 77 aa
MW: 9.810 KDa
KDa: Kilo Dalton. MW: Molecular weight. N: amino acid number.
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pyro-glutamate which prevents the enzymatic destruction of apelins [13, 14]. That is how the biological activity of apelin is preserved. The most widely studied forms of apelin in the heart physiology are apelin-36, apelin-17 and apelin-12 (Table 1) . The numbers next to the word apelin indicate the number of amino acids. It was also identified that [Pyr1] apelin-13 as the predominant isoform in human heart .
block, which is impossible to observe in small cattle supplemented with apelin at the supraphysiological level. Similarly, apelin regulates renal arterial tonus in response to angiotensin II in diabetic mice by increasing NO through endothelial nitric oxide synthase (NOS). Apelin and APJ genes are down-regulated in myocardial injury induced by isoproterenol in rats .
Biochemical and Physiological Effects
Effects on the Fluid Balance
Apelins are important mediators that make cardiovascular homeostasis possible through APJ receptors. APJ receptors are found in the vascular system, endothelial cells, vascular smooth muscle cells and cardiomyocytes. The most potent isoform of apelins is the pyro-glutamine apelin-13. The form which is believed to act on the cardiovascular system is the apelin-36 which contains the highest number of amino acids, as apelin-36 was reported to decrease in chronic pulmonary disease patients who had normal cardiac function where brain natriuretic peptide (BNP) concentrations remained unchanged [6,21,22]. Apelins serve important functions in food intake, insulin secretion, diuresis, cell proliferation, angiogenesis, glucose-fluid balance, vasopressin (anti-diuretic hormone: ADH) release and the balance of the cardiovascular system . The biochemical and physiological effects of apelins are summarized in Fig. 1. Apelins which are strongly inotropic were reported in both animal and human studies to be involved in the pathology of heart failure, which they reportedly do by regulating the function of angiotensin II. Apelin concentration drops in patients with heart failure. However, it was reported to be elevated when the left ventricle was remodeled [6,14,21,22]. Apelin-APJ system was suggested to have a part in the endothelial oxidative system and coronary atherosclerotic plaque formation. A comparison of mice which failed to synthesize both APJ and Apo-E and which were fed on a high-cholesterol diet with mice which failed to synthesize Apo-E only revealed no change in the amount of cholesterol, but a decrease in the amount of atherosclerotic plaque [13,14,23]. The mice which could synthesize neither were found to have a decrease in the markers of oxidative stress and vascular smooth muscle cells. Individuals who had hyper-cholesterolemia were established to have lower plasma apelin levels than the control group.
The role of apelin in the fluid balance is not certain. Animal experiments exploring the effect of apelin on the ADH has produced contradictory results . Apelin is also synthesized in the supraoptic and paraventricular regions of the hypothalamus which play a vital role in the fluid balance through the production of APJ and ADH . Additionally, apelin was shown in the neurons where ADH mRNA is expressed, which suggests that apelin brings about an antidiuretic activity by preventing the release of ADH. Studies on involving animals have produced different results. Intracerebral infusion of apelin to rats caused a decrease in dehydration by reducing the circulating ADH and thereby inducing fluid intake. The effect of APJ and apelin on liquid intake and urinary electrolyte concentrations in knock-out mice is different than that in conscious mice . Although the role of apelin and APJ system in relation to the cardiovascular balance and fluid balance have been investigated through interesting questions in all these studies, there is still a need for numerous other studies to determine the exact effect of apelin on cardiophysiology at the local and synthetic level.
At the same time, assuming the role of a co-receptor for human immune virus (HIV) 1 apelin prevents the settlement of the virus in APJ and thus inhibits the viral entry of HIV 1 into cluster of differentiation (CD4+) cells . Apelin injection increases water intake . Additionally, apelin reduces the release of the anti-diuretic hormone vasopressin in the hypothalamus. The diuretic effect of apelin is associated with its hypotensive action, which plays a significant role in the homeostatic balance of body fluids . Apelin was also detected in the appetite-controlling centers of like brain and there is in an inverse correlation with appetite . The activation of enterochromaffine-like cells by the apelin secreted from the parietal cells of the stomach inhibits the release of histamine from these enterochromaffine-like cells . Apelin also regulates the migration of progenitor cells of the heart in the early embryologic period by differentiation of contractile cells and cardiomyocytes possible . Bovine animals were found to have a 50% atrio-ventricular (AV)
Effects on Contractile Activity Apelin is a peptide with a dose-dependent inotropic effect [28-30]. It was reported that when isolated rat hearts were infused with apelin and heart contracted at a constant rate volumetrically, they produced an inotropic response and showed an increased peak rate in left ventricular pressure. In vivo pressure and volume measurements in rats and mice were confirmed with similar results. Moreover, chronic apelin replacement in conscious normal mice brought about an increase in cardiac output and circumferential contraction, which could also be detected by echocardiography, without causing myocardial hypertrophy [31,32]. Apelin infusion in heart failure induced by an experimental infarction causes an elevation in cardiac contractility to the extent that it can provide a potential treatment to heart failure . The inotropic effects of apelin are not affected by NO synthase inhibition as well [33,34]. Adrenergic signal antagonism or inhibition of endothelin receptors depend on cardiac innervation. It is believed that rather than increasing the calcium sensitivity in microfilaments, apelin exercises its inotropic effect by increasing the amount of intracellular calcium. This elevated contractility may be a more effective factor in myocardial failure. Although phospholipase-C, protein kinase-C, sarcolemmal hydrogen (H), sodium (Na+) and calcium (Ca2+) exchangers contain (Ca2+), it is not known how the amount of Ca2+) increases . Points to Consider in Apelin Analyses in Biological Fluids and Tissues MEROPS data show that there are more than 700 proteases in the human genome . The definitions of the pro-
The Role of Apelins in the Physiology of the Heart
Protein & Peptide Letters, 2014, Vol. 21, No. 1
The main Apelins sources Adipoytes; Artery and Veins; Osteoblasts Heart, Placenta, Lung, Kidneys, Pineal gland, Pituitary, Arcuate nucleus, and Supraoptic (SON) nuclei and Paravebtricular nucleus (PVN) of the hypothalamus
The main physiological and biochemical effects of Apelins Inotropic effects ; Angiogenesis ; Retinal vascular development ; Vasodilation
; Vasoconstriction ; Diuresis ; Gastric cell proliferation ;
Cholecystokinin secretion ; Recovery of ischemia ; Inflammation ; Insulin sensitivity ; Food intake ; Blood pressure ; Vasopressin ; Insulin secretion ; Adiposity ; Apoptosis ; Drinking water ; Required of cardiovascular development, modulation of vascular tone and immunity, regulation of gastric acid secretion and ischemia rep erfusion injury.
Figure 1. Major sites of synthesis and biological effects of apelins.
tein and peptide notions are not clear. However, structures which contain 50 or fewer amino acids are called peptides, while those which have more than 50 amino acids are called proteins . Hormones in protein structure are rapidly broken down by cell proteases. Since the number of amino acids that apelins contain is fewer than 50, protease inhibitors should be used to protect them against proteases. In general, using a protease inhibitor (aprotinin) of 500 kallikrein inhibitor unit (KIU) is recommended per milliliter of biological samples. The significance of using protease inhibitors to protect peptides against proteases was reported by other independent researchers too [38,39]. Apelins can be measured by Enzyme linked Immunosorbent Assay (ELISA) and Radio immuno assay (RIA) methods. When working with apelins in tissue samples, proteases activity should be inactivated by boiling the sample tissue in a water bath for 5 to 10 minutes. In this way, the samples can be kept stable for about one year at -30 and -80oC [40,41].
sure and blood pressure. In vitro myographic studies showed that apelin caused venoconstriction in saphenous veins whose endothelium was removed and NO-dependent vasorelaxation in human mesenteric arteries [33,34]. Furthermore, apelin was reported to cause reversible vasodilation in forearm resistant vessels, just like it did in human mesenteric vessels, in in vitro preclinical models . Both isoforms of apelin, apelin-36 and apelin-13, were shown to lead to vasodilation . Although apelin-36 exhibited a slower performance, its vasodilative effect continued for at least 42 minutes after the infusion was discontinued. This unusual, prolonged effect was shown with desmopressin, a V2 agonist, as well . Apelin-36 acts slower than apelin-13. The clearance of apelin from the circulation takes 8 minutes at most. Administration of apelin to patients in in vivo conditions causes NO-mediated arterial vasodilation without any marked effect on peripheral venous tonus [8,43]. Apelin infusions do not cause any serious side effects and are very well tolerated [14,15].
Effects on the Cardiovascular System
Results obtained from preclinical models indicate that apelin-APJ system has critical effects on cardiovascular homeostasis . Experimental animal models show that apelin-
Exogenous administration of apelin to rodents caused a rapid, NO dependent fall in the mean capillary filling pres-
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APJ system has a part in cardiovascular fluid homeostasis [42,44]. A strong inotropic, a vasodilator and a facilitator of fluid homeostasis, apelins are a new peptide that can play a part in the target therapies of heart failure [6,15,20-22]. What is more, unlike the angiotensin II and angiotensin I pathway, apelin-APJ systems possess characteristics that can set new alternative treatment objectives targeting the heart failure mechanism . Changes in Coronary Artery Bypass In the study which was carried off pump and on pump, it was reported that the concentration of the natriuretic peptides, apelin and adrenomedullin significantly increased in the post-operative period and that natriuretic peptides continued to increase markedly in the post-op day 5 . Furthermore, troponin-I was elevated significantly after the on pump coronary artery bypass also stated that there was no difference between the off pump and on pump levels of the natriuretic peptide, adrenomedullin and apelin . It was shown by immunohistochemistry that apelin was synthesized in the endothelial cells of the intima and fibroblast cells of the media of the aorta, while in only the smooth muscle cells of the media of left internal mammary artery (LIMA) and saphena . ELISA measurements revealed similar levels of apelin-36 in aorta and LIMA tissues; while apelin expression of saphena tissue was lower than that of both (aorta and LIMA) tissues . These results are consistent with the reported presence of mRNA and apelin receptors in human and rat myocardium, medial layer of the coronary artery, saphena and aorta [46,47]. All these data demonstrate that although apelins play a critical role in the physiology of the heart, cardiopulmonary bypass and coronary artery bypass grafting. It was also shown that apelin-36 gradually decrease after anesthetic induction, followed by a gradual increase after the patients’ admission to intensive care unit and reach the levels before the induction of anesthesia . Effects on Vascular Tonus There is no consensus on the effects of apelin on vascular tonus in the physiologic experiments performed on anesthetized or conscious mice [14,15]. Although it is claimed to be a vasoconstrictive, intravenous apelin administration to anesthetized rats exercised an NO-mediated vasodilative effect without impacting the heart rate and caused a decrease in systolic and diastolic pressure. The drop in blood pressure was dose-dependent to a large extent and in an inverse relationship with molecular size; additionally, when an NO synthesis inhibitor was administered before treatment, apelin produced the opposite effect and led to contraction [33,34]. Thus, this effect was proven to be an NO-mediated indirect effect . In conscious rodents, when ganglionic inhibition was removed, apelin was reported to function as a venous and arterial dilatator in vivo and to cause moderate tachycardia. This implies that apelin is an NO-mediated peripheral vasodilator . It increases the heart rate not directly through a chronotropic effect, but secondary to the baroreceptor reflex. Apelin brings about opposite effects in conscious sheep and anesthetized and conscious rats and causes an increase in the mean arterial pressure and heart rate .
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It was reported in bovine models that intravenous apelin-13 created a biphasic response in mean arterial blood pressure and heart rate and this biphasic response consisted of a preliminary decrease, followed by a momentary increase and a decline back to the baseline level in the last 15 minutes . The right atrial pressure is elevated and a parallel elevation occurs in natriuretic peptides. In vitro experiments indicate that apelin can function as a vasodilator and vasoconstrictor [6,13,14]. The mechanism of the arterial vasodilation caused by apelin in isolated rat hearts was attributed to NO synthase/NO pathways of L-arginine. APJ is synthesized in the vascular smooth muscles of rats. Apelin led to vasodilation in the saphenous vein which does not have a functional endothelium by causing phosphorylation in the myosin light chain. Apelin exercises all its effects on the vascular smooth muscle tissue through the mediation of NO produced in the endothelium [33,34]. In consideration of the effects of apelin on vascular tonus under in vivo circumstances, it was argued that there might be a dynamic connection between apelinAPJ and angiotensin-I and angiotensin-II (AT-II) [6,13,14]. All-transretinoic acid regulating the G protein receptor signals in hypertensive mice reduces the blood pressure and increases the expression of apelin and APJ in the aorta . These occur together with an increase in NO and a decline in angiotensin-I expression. Apelin does not directly act upon rat portal veins. In cases without an endothelium, apelin eliminates the vasoconstrictor response to angiotension-II through an NO-dependent mechanism [33,34]. The effect of APJ on the basal blood pressure in knockout mice is not different than that in other groups. However, knockout mice produce an enhanced vasopressor response to angiotensin-II . The modification of the normal connection in apelin and AT-II in disease situations has been attributed to the ailed mice . It was reported that in the aorta of diabetic mice where APJ expression was reduced, contractile response to AT-II increased and relaxation was curtailed with acetylcholine [6,13,14]. Effects on Ventricular Dysfunction Ventricular apelin mRNA was found elevated in heart failure secondary to ischemic heart disease and dilated cardiomyopathy . In this study, APJ receptor mRNA was found lower in patients with dilated cardiomyopathy, and this suggests that APJ apelin pathway is involved in the pathogenesis of heart failure in humans. Plasma concentrations of apelin in chronic heart failure patients were found lower than those in the normal control groups . It was reported in another study that dilated cardiomyopathy was caused by the defect in the APJ receptor gene . Although there are conflicting results about the actual role of apelinAPJ system in the pathogenesis of heart failure, scientific data in general suggest that apelin decreases in heart failure and is up-regulated in left ventricular re-modeling [6,13,14]. It is yet no known whether the main source of these observed changes in apelin amount is the cardiac tissue or peripheral tissue. The interaction between the apelin-APJ system and other neuro-hormonal systems has a part in the pathogenesis of heart failure [6,13,14].
The Role of Apelins in the Physiology of the Heart
Protein & Peptide Letters, 2014, Vol. 21, No. 1
Vascular expression of apelin receptors is involved in the control of blood pressure, but this activation triggers the formation of new vessels . The receptors which carry out the hypotensive action of apelin are expressed in the endothelium. The activation mentioned here is an indirect one spurred by the release of NO, which is a potent vasodilator [33,34]. Studies involving mice whose apelin receptor genes were removed reported a balance between the signals of angiotensin-II which increases blood pressure and apelin which reduces blood pressure . It has been argued that angiogenic activity results from the effect of apelin on the proliferation and migration activities in the endothelial cells. Apelin activates intracellular conduction systems in a way that will ensure the proliferation of endothelial cells and new blood vessel formation [6,13,14]. Besides, a delay was observed in the formation of retinal vessels when the apelin gene was removed .
Apelin and angiotensin-like 1 receptor
Brain natriuretic peptide
Anti-diuretic hormone (Vasopressin)
Human immune virus
Nitric oxide synthase
Changes in Myocardial Ischemia It has been reported in in vivo and in vitro studies that apelin and APJ gene expressions were regulated in response to hypoxia in the peripheral and cardiac tissues [56-58]. Apelin and APJ expressions were found elevated in the rat models of experimental myocardial infarction (MI). Exogenous apelin infusion increases cardiac contractility. When apelin was administered exogenously, endogenous synthesis of APJ receptors was found inadequate. Consequently, it was argued that the induction of the apelin-APJ system to alleviate the myocardial damage in ischemia could be useful, and that in this way, myocardium could be protected in ischemia reperfusion injury [6,13,14,56,57].
Enzyme-linked Immunosorbent Assay
CONFLICT OF INTEREST The authors have not disclosed any potential conflicts of interest. ACKNOWLEDGEMENT Declared none. REFERENCES   
CONCLUSION Many peptide hormones including salusin and apelin are involved in the regulation of blood pressure [2,59,60]. Despite the use of up to three different anti-hypertensive drugs (one of them being a diuretic), efforts to decrease the blood pressure below 140/90 mmHg in the general population end in failure 15 to 27% of the time (resistant hypertension) . Although this failure is attributed to a number of reported reasons including resistance to anti-hypertensive treatment, both false (false measurement, white coat effect, noncompliance with the treatment and pseudo-hypertension) and real (excessive salt intake, oral contraceptives, herbs, use of alcohol, obesity, etc.), it is yet to be uncovered whether the peptides involved in the vascular system and pressure regulation have a part in the development of resistant hypertension (RH) . In the light of the data compiled in this review, it is suggested that there may be a correlation between the amounts of apelins of various forms and other vasoactive peptides released to the circulation and the development of cardiovascular system homeostasis and resistant hypertension. Disruption of the balance between the vasodilator and vasoconstrictive peptides, as in the case of changes in the circulating levels of apelins, strengthens the hypothesis that they might be involved in the development of resistant hypertension.
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Received: November 6, 2012
Protein & Peptide Letters, 2014, Vol. 21, No. 1
Revised: February 19, 2013
Accepted: February 25, 2013
Japp, A.G.; Cruden, N.L.; Barnes, G.; van Gemeren, N.; Mathews, J.; Adamson, J.; Johnston, N.R.; Denvir, M.A.; Megson, I.L.; Flapan, A.D.; Newby, D.E. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation, 2010, 121, 1818-1827. Gurzu, B.; Petrescu, B.C.; Costuleanu, M.; Petrescu, G. Interactions between apelin and angiotensin II on rat portal vein. J. Renin. Angiotensin Aldosterone Syst., 2006, 7, 212-216. Ti, Y.; Wang, F.; Wang, Z.H.; Wang, X.L.; Zhang, W.; Zhang, Y.; Bu, P.L. Associations of serum salusin-alpha levels with atherosclerosis and left ventricular diastolic dysfunction in essential hypertension. J. Hum. Hypertens., 2012, 26, 603-609. Chandrasekaran, B.; Kalra, P.R.; Donovan, J.; Hooper, J.; Clague, J.R.; McDonagh, T.A. Myocardial apelin production is reduced in humans with left ventricular systolic dysfunction. J. Card. Fail., 2010, 16, 556-561. Anadol, Z.; Discigil, G. [Factors affecting treatment compliance in Hypertensive Patients]. Turkiye Klinikleri J. Cardiovasc. Sci., 2009, 21, 184-190.