Cardiac Excitation-Contraction Coupling by p38 MAPK

MAPK超家族是所有真核生物中最重要的信号转导系统之一。确定了三个主要亚群，包括细胞外信号调节激酶（ERK1/2）， p38 MAPK和c-jun- nh2末端激酶（JNK）。p38 MAPK是最古老的信号分子之一，参与多种细胞过程，包括细胞增殖、细胞生长和细胞死亡。

MAPK superfamily is one of the most important signal transduction systems conserved in all eukaryotes. There are three major subgroups identified, including the extracellular signal regulated kinase (ERK1/2), p38 MAPK and c-jun-NH2terminal kinase (JNK). p38 MAPK is one of the most ancient signaling molecules involved in multiple cellular processes, including cell proliferation, cell growth and cell death. In the heart, activation of p38 MAPK has been observed in pressure-overload or ischemia/infarction induced cardiac hypertrophy and heart failure in humans and animal models. In cultured cardiac myocytes, activation of p38 MAPK induces myocyte hypertrophy and apoptosis, and is also implicated in the preconditioning process and ischemia/reperfusion injury. Increasing evidence suggests that inhibition of p38 MAPK is able to improve cardiac contractility in ischemia/reperfusion-injured hearts. The specific goal of this research program is to determine whether p38-MAPK activation modulates cardiac myocyte excitation-contraction coupling and if so, to explore the possible underlying mechanisms. We have examined the possible effects of p38-MAPK activation or inhibition on cardiac contractility at the single cell level, and verified the conclusion obtained from single myocyte experiments by in vivo studies in transgenic mice overexpressing activated mutants of p38 MAPK upstream kinases. In addition, we have examined the potential interaction between AR and p38 MAPK signaling pathways in regulating cardiac contractility, and the pathophysiological relevance of p38 activation in ischemic contractile dysfunction and cardiomyocyte injury. Our in vivo and in vitro studies have demonstrated, for the first time, that inhibition of p38 MAPK leads to a positive inotropic effect, whereas enhanced p38 MAPK activation inhibits myocyte contractility and negates AR/PKA-mediated positive inotropic effect. Furthermore, we have shown that inhibition of ischemia-induced, intracellular acidosis-mediated activation of p38 MAPK not only protects myocytes against ischemic death but also reverses ischemic contractile dysfunction. These findings reveal a novel function of p38 MAPK, and provide new insights for a better understanding of the coincidence of enhanced p38 MAPK signaling and cardiac contractile dysfunction under certain pathophysiological conditions, such as cardiac ischemic/reperfusion injury and chronic heart failure.