Direct effects of apelin on cardiomyocyte contractility and electrophysiology

doi:10.1016/j.bbrc.2007.04.017

Biochemical and Biophysical Research Communications

Volume 357, Issue 4, 15 June 2007, Pages 889-895

https://doi.org/10.1016/j.bbrc.2007.04.017 Get rights and content

Abstract

Apelin, the ligand for the angiotensin receptor like-1, has been implicated in the pathogenesis of atrial fibrillation and heart failure. However, it is unknown if apelin has direct effects on cardiomyocyte contractility and electrophysiology. APJ-like immunoreactivity was localized to T-tubules and intercalated disc area in isolated adult rat ventricular myocytes. Apelin (1 nM) significantly increased sarcomere shortening in normal as well as failing cardiomyocytes. The transient increase in shortening was not accompanied by increased [Ca²⁺] transient amplitude. Apelin significantly activated the sarcolemmal Na⁺/H⁺ exchanger (NHE) and increased intracellular pH. Moreover, apelin (10 nM) increased conduction velocity in monolayers of cultured neonatal rat cardiac myocytes. Our results demonstrate for the first time that apelin has direct effects on the propagation of action potential and contractility in cardiomyocytes. One of the mechanisms involved in the inotropic effect may be an increased myofilament sensitivity to Ca²⁺ as apelin enhanced the activity of NHE with consequent intracellular alkalinization.

Section snippets

Materials and methods

Cell isolation and failing heart model. All animal procedures were performed in accordance with the UK Animal (Scientific Procedures) Act 1986. Rat cardiomyocytes were enzymatically isolated as previously described [18]. Heart failure was obtained in rats 8 weeks after left coronary artery ligation. Briefly, through a left-sided thoracotomy, the left coronary artery was permanently ligated at the level of the left atrial appendage using a 6-0 suture to cause myocardial infarction and subsequent

Cellular localization of the APJ receptor

Confocal immunofluorescence microscopic imaging confirmed the presence of APJ receptor-like immunoreactivity in isolated adult ventricular myocytes and in heart tissue [8]. APJ receptor-like immunoreactivity was detected in a transversal striated distribution associated with T-tubules (Fig. 1) and in the intercalated disc area (Fig. 1A, B, D, and E).

Effect of apelin on cardiomyocyte contractility

In isolated perfused rat hearts, apelin has been shown to induce maximal positive inotropic effect at concentrations of 1 and 10 nM [7]. As shown in

Discussion

The cellular mechanisms underlying the ex vivo[7] and in vivo effects of apelin on left ventricular function [9], [10] required further investigation. The present study provides the first direct evidence for a positive inotropic effect of apelin in adult ventricular myocytes. Our results suggest that the positive inotropic effect of apelin is due to stimulation of the sarcolemmal NHE, leading to intracellular alkalinization and, possibly, increased myofilament sensitivity to Ca²⁺. In contrast

Acknowledgments

We thank the Magdi Yacoub Institute, the British Heart Foundation, the Welcome Trust, and the Cromwell fellowship at Imperial College for financial support.

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Citation Excerpt :
In a murine model of right ventricle HF, apelin administration enhanced contractility, which happened in response to higher Ca2+ transients instead of changes in filament sensitization [110]. However, a later study using isolated cardiomyocytes showed that apelin does alter filament sensitization via NHE-mediated alkalinization [111]. Apelin’s effects on myocardial contractility also involve independent modulation of PKC and ERK, providing another route for myofilament sensitization [44].
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Direct effects of apelin on cardiomyocyte contractility and electrophysiology

Abstract

Section snippets

Materials and methods

Cellular localization of the APJ receptor

Effect of apelin on cardiomyocyte contractility

Discussion

Acknowledgments

Gene

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochim. Biophys. Acta

Regul. Pept.

Pharmacol. Ther.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

J. Mol. Cell Cardiol.

J. Biol. Chem.

Eur. J. Pharmacol.

Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity

Physiol. Rev.