Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions of the brain. A growing body of evidence now demonstrates a regulatory role for the apelin/APJ receptor system in cardiovascular physiology and pathophysiology, thus making it a potential target for cardiovascular drug discovery and development. Indeed, ongoing studies are investigating the potential benefits of apelin and apelin-mimetics for disorders such as heart failure and pulmonary arterial hypertension. Apelin causes relaxation of isolated arteries, and systemic administration of apelin typically results in a reduction in systolic and diastolic blood pressure and an increase in blood flow. Nonetheless, vasopressor responses and contraction of vascular smooth muscle in response to apelin have also been observed under certain conditions. The goal of the current review is to summarize major findings regarding the apelin/APJ receptor system in blood vessels, with an emphasis on regulation of vascular tone, and to identify areas of investigation that may provide guidance for the development of novel therapeutic agents that target this system.
Abstract-The peripheral apelin system plays a significant role in cardiovascular homeostasis and in the pathophysiology of cardiovascular diseases. However, the central effect of this neurohormonal system in neural control of cardiovascular function remains poorly understood. Thus, this study was undertaken to evaluate the effect of apelin in the rostral ventrolateral medulla (RVLM) on blood pressure, cardiac function, and sympathetic nerve activity. Apelin mRNA and protein levels were detected with real-time RT-PCR and Western blots, respectively. Expression of apelin was significantly enhanced in the RVLM of spontaneously hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. To study the functional consequence of upregulated apelin expression, apelin was overexpressed by bilateral microinjection of the AAV2-apelin viral vector into the RVLM of WKY rats. Immunofluorescence staining and Western blots demonstrated that microinjection of AAV2-apelin into the RVLM resulted in a significant increase in apelin expression, which was associated with a chronic elevation in blood pressure and cardiac hypertrophy. In addition, direct microinjection of exogenous apelin-13 (200 pmol in 50 nL) into the RVLM caused a 20 mm Hg elevation in blood pressure and a 24% increase in sympathetic nerve activity. The present study is the first to show that apelin expression is enhanced in the RVLM of SHR versus WKY rats and that overexpression of this gene in the RVLM results in chronic blood pressure elevation and cardiac hypertrophy in normotensive rats. Thus, the apelin system in the RVLM may play a very important role in central blood pressure regulation and in the pathogenesis of hypertension. Key Words: blood pressure Ⅲ hypertension Ⅲ hypertrophy Ⅲ brain Ⅲ sympathetic A pelin is a peptide recently isolated from bovine stomach extracts. 1 It has been identified as the endogenous ligand for the orphan G protein-coupled receptor APJ, 1,2 which is comprised of 7 transmembrane domains and shares a 31% amino acid sequence identity to the angiotensin II type 1 receptor. 3 Despite the degree of homology between these receptors, angiotensin (Ang) II does not bind the APJ receptor, and apelin is the only known ligand for the APJ receptor. 3 Multiple apelin peptides appear to be derived from a 77-aa precursor peptide, including preproapelin apelin-36 (42-77), apelin-17 (61-77), and apelin-13 (65-77). Apelin and APJ are widely distributed in various tissues and are thought to be involved in cardiovascular regulation, 4,5 heart contractility, body fluid homeostasis, 6 control of appetite, and, possibly, immune functions. 7 The role of apelin and APJ in the cardiovascular system is currently the best documented. The accumulated evidence indicates that apelin and its APJ receptor are expressed throughout the cardiovascular system. Both pressor and depressor responses have been described in response to peripheral administration of apelin. 1,5,8 -10 Genetic studies in humans also demonstrate that disruption of the endogenous ...
Sun C. 20-HETE increases NADPH oxidase-derived ROS production and stimulates the L-type Ca 2ϩ channel via a PKCdependent mechanism in cardiomyocytes. Am J Physiol Heart Circ Physiol 299: H1109 -H1117, 2010. First published July 30, 2010; doi:10.1152/ajpheart.00067.2010.-The production of 20-hydroxyeicosatetraenoic acid (20-HETE) is increased during ischemia-reperfusion, and inhibition of 20-HETE production has been shown to reduce infarct size caused by ischemia. This study was aimed to discover the molecular mechanism underlying the action of 20-HETE in cardiac myocytes. The effect of 20-HETE on L-type Ca 2ϩ currents (ICa,L) was examined in rat isolated cardiomyocytes by patch-clamp recording in the whole cell mode. Superfusion of cardiomyocytes with 20-HETE (10 -100 nM) resulted in a concentration-dependent increase in I Ca,L, and this action of 20-HETE was attenuated by a specific NADPH oxidase inhibitor, gp91ds-tat (5 M), or a superoxide scavenger, polyethylene glycol-superoxide dismutase (25 U/ml), suggesting that NADPH-oxidase-derived superoxide is involved in the stimulatory action of 20-HETE on ICa,L. Treatment of cardiomyocytes with 20-HETE (100 nM) increased both NADPH oxidase activity and superoxide production by approximately twofold. To study the molecular mechanism mediating the 20-HETE-induced increase in NADPH oxidase activity, PKC activity was measured in cardiomyocytes. Incubation of the cells with 20-HETE (100 nM) significantly increased PKC activity, and pretreatment of cardiomyocytes with a selective PKC inhibitor, GF-109203 (1 M), attenuated the 20-HETE-induced increases in I Ca,L and in NADPH oxidase activity. In summary, 20-HETE stimulates NADPH oxidase-derived superoxide production, which activates L-type Ca 2ϩ channels via a PKC-dependent mechanism in cardiomyocytes. 20-HETE and 20-HETE-producing enzymes could be novel targets for the treatment of cardiac ischemic diseases.20-hydroxyeicosatetraenoic acid; L-type calcium channel; protein kinase C; cardiac myocytes; reactive oxygen species 20-HYDROXYEICOSATETRAENOIC ACID (20-HETE) is a lipid metabolite of arachidonic acid that is produced by -hydroxylase enzymes of the cytochrome P-450 (CYP)4A and CYP4F families, which are relatively abundant and exert regulatory functions dependent on the tissue (18). For example, in the kidney, 20-HETE regulates renal functions, such as renal vascular tone, tubuloglomerular feedback, autoregulation of renal blood flow, tubular transport, and mitogenesis (20). In blood vessels, 20-HETE is a potent vasoconstrictor that activates L-type Ca 2ϩ channels and inhibits Ca 2ϩ -sensitive K ϩ channels in vascular smooth muscle cells (28,29). In pulmonary arteries, 20-HETE enhances NADPH oxidase-dependent production of ROS in endothelial cells (21). Thus, it was proposed that 20-HETE plays an important role in the control of apoptosis and angiogensis in vascular endothelial cells in the pulmonary microcirculation (13). Recently, 20-HETE and CYP -hydroxylase were also identified in hearts from the rat and dog (13,26...
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