Paracrine regulation of cardiac contractility by endogenous endothelin-1

István Szokodi received his M.D. degree from the Medical University of Pécs, Hungary. He has started his scientific carrier under the supervision of Alexander Juhász-Nagy and Miklós Tóth at the Department of Cardiovascular Surgery of the Semmelweis University of Medicine. After receiving his PhD degree in 1998, he continued his work as a postdoctoral fellow in the research group of Heikki Ruskoaho at the Department of Pharmacology and Toxicology, University of Oulu, Finland. He returned to Hungary in 2003 to establish his own research group at the Heart Institute of the University of Pécs, Hungary, where he is currently an Associate Professor. His major research interests include cellular and molecular mechanisms of myocardial contractility and signal transduction of cardiac hypertrophy. As recognition of his scientific achievements, he has received the postdoctoral fellowship of the Academy of Finland, the György Gábor Award for Young Scientists (György Gábor Foundation), the Zoltán Magyary Postdoctoral Fellowship (Zoltán Magyary Higher Educational Public Foundation) and the János Bólyai Research Fellowship (Hungarian Academy of Sciences).

Abstract

Congestive heart failure is a major cause of morbidity and mortality despite recent advances in medical therapy. Therefore, there is an urgent need to identify novel signaling mechanisms regulating myocardial contractility. Endothelin-1 (ET-1) and its cognate receptors (ETA and ETB endothelin receptors) are expressed in the myocardium and the peptide is a potent stimulator of cardiac contractility. However, the functional significance of endogenous ET-1 and the underlying signaling mechanisms are still elusive in the heart. We have shown that two members of the mitogen-activated protein kinase (MAPK) family play opposing roles in the acute regulation of cardiac contractility, as the extracellular signal-regulated kinase 1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. We have provided evidence that endogenous ET-1 is a key mediator of the Gregg effect in mouse hearts. Furthermore, we have demonstrated that endogenous ET-1 plays a prominent role in the maintenance of cardiac function under pathophysiological conditions via modulation of the Frank-Starling response in rat hearts.