Apelin Increases Cardiac Contractility via Protein Kinase C epsilon- and Extracellular Signal-Regulated Kinase-Dependent Mechanisms

作者：Perjes Abel; Skoumal Reka; Tenhunen Olli; Konyi Attila; Simon Mihaly; Horvath Ivan G; Kerkela Risto; Ruskoaho Heikki; Szokodi Istvan^*

来源：PLos One, 2014, 9(4): e93473.

DOI：10.1371/journal.pone.0093473

Background: Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin. %26lt;br%26gt;Methods and Results: In isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKC epsilon, but not PKC alpha, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity. %26lt;br%26gt;Conclusions: Apelin increases cardiac contractility through parallel and independent activation of PKCe and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKC epsilon and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure.

• 出版日期2014-4-2