Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia

Abstract

Rastaldo R, Cappello S, Folino A, Berta GN, Sprio AE, Losano G, Samaja M, Pagliaro P. Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. Am J Physiol Heart Circ Physiol 300: H2308 -H2315, 2011. First published March 4, 2011 doi:10.1152/ajpheart.01177.2010.-We studied whether apelin-13 is cardioprotective against ischemia/reperfusion injury if given as either a pre-or postconditioning mimetic and whether the improved postischemic mechanical recovery induced by apelin-13 depends only on the reduced infarct size or also on a recovery of function of the viable myocardium. We also studied whether nitric oxide (NO) is involved in apelin-induced protection and whether the reported ischemia-induced overexpression of the apelin receptor (APJ) plays a role in cardioprotection. Langendorffperfused rat hearts underwent 30 min of global ischemia and 120 min of reperfusion. Left ventricular pressure was recorded. Infarct size and lactate dehydrogenase release were determined to evaluate the severity of myocardial injury. Apelin-13 was infused at 0.5 M concentration for 20 min either before ischemia or in early reperfusion, without and with NO synthase inhibition by N G -nitro-L-arginine (L-NNA). In additional experiments, before ischemia also 1 M apelin-13 was tested. APJ protein level was measured before and after ischemia. Whereas before ischemia apelin-13 (0.5 and 1.0 M) was ineffective, after ischemia it reduced infarct size from 54 Ϯ 2% to 26 Ϯ 4% of risk area (P Ͻ 0.001) and limited the postischemic myocardial contracture (P Ͻ 0.001). L-NNA alone increased postischemic myocardial contracture. This increase was attenuated by apelin-13, which, however, was unable to reduce infarct size. Ischemia increased APJ protein level after 15-min perfusion, i.e., after most of reperfusion injury has occurred. Apelin-13 protects the heart only if given after ischemia. In this protection NO plays an important role. Apelin-13 efficiency as postconditioning mimetic cannot be explained by the increased APJ level. APJ receptor; ischemia/reperfusion; myocardial protection; preconditioning APELIN IS THE ENDOGENOUS LIGAND for the G protein-coupled APJ receptor. Human, mouse, rat, and cow apelin genes encode a 77-amino acid preprotein with the active sequence in the COOH-terminal region (19,43). Various fragments of apelin have been isolated and classified according to the number of amino acids. Among fragments, apelin-13 and -36 are the most frequently studied, and apelin-13 is considered the most active of them (40). Apelin receptors APJ have been found to be similar to angiotensin II receptor type 1 (25,30,43), but angiotensin II does not bind to APJ receptors (14, 30).Apelin mRNA is expressed in several organs and tissues. In the cardiovascular system, apelin and APJ receptors occur in vascular smooth muscle, endothelial cells, and cardiomyocytes (21,22). Apelin exerts a positive inotropic effect (2, 42) and a nitric oxide (NO)-driven vasodilator activity (14, 15). It protect...

Effects of apelin on the cardiovascular system

“…On the contrary, it remained unchanged if the infusion started 5 min before the onset of reperfusion and ended before removing the occlusion, suggesting that apelin mimics PostC rather than PreC. The hypothesis was confirmed by Rastaldo et al [41], in Langendorff isolated rat heart preparation perfused with 0.5 M apelin-13 buffer for 20 min before or after the end of a 30 min global ischemia. While no protection was seen when apelin was given before ischemia, significant reductions of infarct size and improvement of postischemic mechanical recovery were obtained when apelin was given at the beginning of reperfusion.…”

“…The antagonism of apelin towards RAS indicates that the former displays an important protective effect against cardiac remodelling after myocardial infarction (MI). As it will be discussed later in the present review, the treatment with apelin immediately after an ischemic insult can attenuate the injury during early reperfusion [41]. Thus, the fact that apelin can limit the immediate and delayed consequences of myocardial ischemia underscores its possible role the treatment of coronary artery disease.…”

“…In isolated perfused rat hearts, infusion of apelin-16 produced a progressive dose-dependent (from 1 pM to 10 nM) increase in developed tension which reached its peak (69%) in 24 min [74]. On the contrary, in similar rat heart preparations, a 20 min apelin-13 infusion (500 nM) produced an immediate increase by about 18% in developed pressure, which was back to the control 3 min later only [41]. These data are consisted with what observed in trabeculae, where apelin-12 induced a transient (1 -2 min) increase in developed force by about 7,4% [79].…”

“…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].…”

Role of three adipokines in metabolic syndrome

“…In addition to these basic effects, other important activities of apelin have been reported, such as protection of the myocardium against ischemia-reperfusion injury, 5 inhibition of apelin, it cannot be excluded that an antiangiotensin effect may depend on the activation of the angiotensin converting enzyme-2, which converts angiotensin I and angiotensin II into the nonvasocontrictor angiotensin 1-7 and angiotensin 1-9, respectively. After 6 weeks of treatment, the authors observed a nonsignificant decrease in plasma apelin concentrations in nonobese hypertensive patients, while an increase was observed in all obese hypertensive patients.…”