[Pyr ¹ ]Apelin-13 Identified as the Predominant Apelin Isoform in the Human Heart

Abstract

Abstract-Apelin receptors, present on vascular smooth muscle cells, endothelium, and cardiomyocytes, are activated by the family of apelin peptides to elicit cardiovascular effects in experimental animals, but functional activity in humans has not been studied in detail. We detected low levels of apelin immunoreactivity in plasma of volunteers consistent with an autocrine/paracrine action and detected apelin immunoreactivity in the supernatant from human cultured endothelial cells. We found that [Pyr 1 ]apelin-13 was the predominant isoform in cardiac tissue from patients with coronary artery disease. We tested the hypothesis that apelins have vascular and cardiac actions in human tissues in vitro and compared responses to [Pyr 1 ]apelin-13, apelin-13, and apelin-36. In endothelium-intact mammary artery, all 3 of the apelins induced concentration-dependent vasodilatation with comparable potency (EC 50 : 0.6 to 1.6 nM; maximum response: 40% to 50%). Vasodilatation was abolished after endothelial removal or preincubation with indomethacin but was unaffected by preincubation with N G -nitro-L-arginine methyl ester, indicating involvement of prostanoids but not NO in dilatation by apelins in this patient group. Apelins were potent constrictors of endothelium-denuded saphenous vein (EC 50 : 0.6 to 1.6 nM; maximum response: 17% to 26%) and mammary artery ([Pyr 1 ]apelin-13; EC 50 : 0.2 nM; maximum response: 29%). In paced atrial strips, all 3 of the peptides increased the force of contraction with subnanomolar potencies (EC 50 : 40 to 125 pM). For the first time, we demonstrate that the 3 principal forms of apelin have comparable potency and efficacy in human cardiovascular tissues. Apelins are potent endothelium-dependent vasodilators acting via a prostanoid-dependent mechanism; however, removal of the endothelium revealed direct vasoconstrictor actions in both the artery and vein. Furthermore, in human cardiac tissue, the apelin peptides are among the most potent endogenous positive inotropic agents yet reported. A pelin peptides, derived from a single gene, activate the G protein-coupled receptor APJ that has high sequence similarity with the angiotensin II type 1 receptor but does not bind angiotensin II. 1,2 The precursor, preproapelin, 2-4 contains several proteolytic cleavage sites, 3 predicting formation of C-terminal peptides, including apelin-36, apelin-13, and [Pyr 1 ]apelin-13, 2,3,5 but the endogenous isoforms in humans remain to be identified. APJ modulates fluid homeostasis 4 -6 and acts as coreceptor for HIV infection, 7,8 and apelin is a novel adipokine 9 -11 with an emerging role in the cardiovascular system. 6,12-38 A role for apelin in human cardiovascular disease has been proposed; importantly, mRNA microarray analysis of Ͼ12 000 genes identified APJ as the most consistently and significantly increased gene in heart failure patients after mechanical offloading. 12 Circulating levels of apelin may be unchanged 13 or raised 12 in early stages of heart failure but were normalized 12 or decreased...

Serum level of apelin-13 negatively correlated with NT-proBNP in heart failure patients

“…Its pyroglutamated form was found to be the predominant form of myocardial apelin in the human heart and plasma [27][28][29][30].…”

Effects of apelin on the cardiovascular system

“…A short lasting inotropic effect was also seen in isolated adult rat cardiomyocytes, where the sarcomere shortening increased for 1 -2 min only in response to apelin-16 superfusion (1-10 nM) and returned to the control before the superfusion was discontinued [17]. The different duration of the effect does not seem to be depend on the different isoforms, because (pyr)apelin-13, apelin-13 and apelin-36 show comparable potency and efficacy in inducing positive inotropic effect [8,75]. On the other hand the importance of different procedures of contractility assessment cannot be disregarded.…”

“…Apelin is reported to potentiate myocardial inotropy in isolated preparations and intact animals [74,24,8,25,17,75,41,69]. For this reason it has been suggested as a tool for the treatment of heart failure (HF) [76,70,24,67,77,78].…”

“…Sartans are a group of hypotensive drugs reported to increase the expression of apelin [11]. The heart, especially atria, and adipose tissue are the predominant sources of plasma apelin in humans [12,8,6]. Apelin-17 and (pyr)apelin-13 have been considered the major isoforms present in human and rat plasma [13,14].…”

“…Apelin-13 and, to a lesser extent, apelin-36 have been considered the most active isoforms with the greatest activity on the cardiovascular apparatus [7,4]. Recently it has been demonstrated that, the predominant isoforms in the heart are apelin-13 and its posttranscriptionally modified form, pyroglutamyl apelin-13 ((pyr)apelin-13), which is obtained from apelin-13 by enzymatic conversion of the N-terminal glutamate residue into pyroglutamate, while apelin-36 is predominant in lung, testis and uterus [6,8]. Immunocytochemistry analysis of human hearts revealed that apelin is expressed in cardiomyocytes and in the vascular and endocardial endothelium [9,10].…”