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...

No abstract

Background and purpose: The aim of this study was to determine whether the apelin/APJ system is altered in human cardiovascular disease by investigating whether the expression of apelin or its receptor is altered at the protein level. Experimental approach: Radioligand binding studies were used to determine apelin receptor density in human cardiac tissues. Apelin peptide levels in cardiovascular tissues were determined by radioimmunoassay. In vitro pharmacology was used to assess vasoactive properties of apelin in human coronary artery. Localization of apelin and its receptor in coronary artery was determined using immunohistochemistry. Key results: Apelin receptor density was significantly decreased in left ventricle from patients with dilated cardiomyopathy or ischaemic heart disease compared with controls, but apelin peptide levels remained unchanged. Apelin was up-regulated in human atherosclerotic coronary artery and this additional peptide localized to the plaque, colocalizing with markers for macrophages and smooth muscle cells. Apelin potently constricted human coronary artery. Conclusions and implications:We have detected changes in the apelin/APJ system in human diseased cardiac and vascular tissue. The decrease in receptor density in heart failure may limit the positive inotropic actions of apelin, contributing to contractile dysfunction. The contribution of the increased apelin levels in atherosclerotic coronary artery to disease progression remains to be determined. These data suggest a potential role for the apelin/APJ system in human cardiovascular disease.