Unlocking the Therapeutic Potential of Apelin.

نویسندگان

  • Alan G Japp
  • David E Newby
چکیده

Apelin was identified in 1998 as the endogenous ligand for the then orphan G-protein–coupled receptor, APJ, now renamed the apelin receptor. Widely expressed in the central nervous system and peripheral tissues, the apelin system participates in a diverse array of processes, including glucose metabolism, immune function, and fluid homeostasis. However, its principal physiological role seems to be related to its cardiovascular actions. Apelin is synthesized as a 77-amino acid prepropeptide that is cleaved into a mature 36-amino acid peptide. Shorter more active isoforms have also been identified, with the pyroglutamated 13-amino acid apelin, (Pyr)apelin-13, being the most potent and abundant form in cardiac tissue. The main source of plasma apelin is unclear although the vascular endothelium and the atria of the heart are likely to be significant contributors. Apelin has a brief plasma half-life of <5 minutes in humans, and its cardiovascular effects are relatively short lived. One enzyme that has long been implicated in the inactivation of apelin peptides is angiotensin-converting enzyme (ACE) type 2, a carboxypeptidase that negatively regulates the renin–angiotensin–aldosterone system by cleaving angiotensin II to the biologically inactive peptide angiotensin 1–9 or angiotensin 1–7. Although ACE2 was previously reported to hydrolyse both apelin-13 and apelin-36 with high catalytic efficiency, its ability to inactivate these peptides and physiological significance was hitherto unclear (Figure). In this issue of Hypertension, Wang et al present a comprehensive series of studies that confirm an important role for ACE2 in the metabolism of biologically active apelin isoforms and represent an important step toward the development of longer acting apelin receptor agonists. Building on elegant molecular modeling studies, the authors convincingly show, through a combination of in vitro and in vivo approaches, that ACE2 contributes to the degradation of both apelin-17 and (Pyr)apelin-13. In mice, the loss of ACE2 function, through either pharmacological inhibition or genetic knockout, prolonged circulating concentrations of both these isoforms after exogenous administration. Importantly, in both models, greater persistence of the apelin peptide was associated with a more sustained depressor response. The authors then proceeded to construct and test 2 apelin analogues designed to be resistant to proteolytic cleavage by ACE2. After confirming the inability of ACE2 to cleave these analogues in vitro, they concluded by demonstrating a prolonged hypotensive action of both analogues relative to the native isoforms. This work could open up new avenues for exploring the therapeutic potential of apelin. In preclinical models, apelin receptor agonism mediates a nitric oxide–dependent fall in blood pressure, reduces ventricular preload and afterload, and potently increases myocardial contractility. These effects are paralleled in humans in whom apelin peptides induce peripheral and coronary vasodilatation while increasing cardiac output and contractility. Importantly, both the local vascular and systemic hemodynamic responses to apelin are preserved in patients with stable symptomatic chronic heart failure, maintained on contemporary medical therapy. In addition to these actions, increasing preclinical evidence also suggests favorable effects on glucose and lipid metabolism, inhibition of atherosclerosis and aneurysm formation, and myocardial protection against ischemia reperfusion injury. Given this favorable profile of physiological actions, the upregulation of apelin signaling may be beneficial in not only many cardiovascular disorders, most notably heart failure, but also vascular disease, hypertension, myocardial ischemia, and the metabolic syndrome. To date, detailed clinical research in this area has been severely hampered by a lack of available tools to study the effects of sustained apelin agonism. One strategy to augment apelin signaling is to inhibit the breakdown of biologically active endogenous apelin peptides. The feasibility and efficacy of such an approach in the setting of heart failure have recently been demonstrated with the neprilysin inhibitor, sacubitril. Inhibition of neprilysin, a neutral endopeptidase, increases circulating concentrations and actions of endogenous natriuretic peptides, bradykinin, and adrenomedullin by reducing their degradation. An alternative strategy is to develop long-acting orally available apelin analogues. One major barrier to progress on both of these fronts has been a poor understanding of the post-translational processing, cleavage, and inactivation of apelin peptides. The studies by Wang et al, therefore, represent an important step toward our ability to study the effects of chronic apelin agonism: a prerequisite for exploring its therapeutic potential. These recent studies have several notable strengths. The use of multiple complementary approaches, including the measurement of cardiovascular responses, increases confidence in the principal findings and enhances their physiological relevance. The authors also used a high-performance mass spectrometry–based method for apelin quantification capable The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Reprint requests to David E. Newby, British Heart Foundation Centre for Cardiovascular Science, Chancellor’s Bldg, University of Edinburgh, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SA. E-mail [email protected] Unlocking the Therapeutic Potential of Apelin

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Effect of apelin on cardiac contractility in acute reno-vascular hypertension: The role of apelin receptor and kappa opioid receptor heterodimerization

Objective(s): Apelin/APJ system plays an important role in the regulation of myocardial contractility (MC) and blood pressure. Opioid receptors (OPRs) are also important cardiovascular regulators and exert many of their effects through modulating the function of other systems. This study analyzed the interaction between APJ and kappa OPRs (KOR) in cardiac responsiveness to apelin in acute reno-...

متن کامل

The Apelin – APJ system : Its role in renal physiology and potential therapeutic applications for renal disease

Abstract Introduction Apelin is a vasoactive peptide isolated as a selective endogenous ligand of orphan receptor, APJ, which was genetically identified to have closest identity to the angiotensin II type 1 (AT-1) receptor. Subsequent studies elucidated the roles of the apelin–APJ system in human physiology, including the regulation of cardiovascular function and fluid homeostasis. In spite of ...

متن کامل

Apelin: A promising therapeutic target? (Part 1)

Apelin is a recently discovered bioactive peptide, known to be an endogenous high-affinity ligandfor the previously orphan G protein-coupled receptor APJ. Apelin/APJ as a novel signaling pathwayhas been shown to play many crucial roles in cardiovascular function, blood pressure regulation, fluidhomeostasis, feeding behavior, obesity, type 2 diabetes mellitus, adipoinsular axis regulation, cellp...

متن کامل

Apelin/APJ system: A key therapeutic target for liver disease

Apelin, a new bioactive peptide, was identified as an endogenous ligand for APJ (Angiotensin II receptor-like 1). Apelin and its receptor have an abundant distribution in central nervous system and peripheral tissues, including liver. Apelin/APJ has diverse physiological and pathological effects, including regulation of cardiovascular function, angiogenesis, fluid homeostasis and so on. Apelin/...

متن کامل

Low Dose of Apelin-36 Attenuates ER Stress-Associated Apoptosis in Rats with Ischemic Stroke

Cerebral ischemia/reperfusion (I/R) injury-induced cellular apoptosis contributes to neuronal death in ischemic stroke, while endoplasmic reticulum stress (ERS) and subsequently triggered unfolded protein response (UPR) are the major mechanisms of cerebral I/R injury-induced apoptosis. A number of studies indicated that apelin-13 protects neurons from I/R injury-induced apoptosis. Apelin-36, th...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Hypertension

دوره 68 2  شماره 

صفحات  -

تاریخ انتشار 2016