Cardiac Excitation-Contraction Coupling by p38 MAPK

MAPK超家族是真核生物中最重要的信号转导系统之一。细胞外信号调节激酶（ERK 1/2）、p38 MAPK和c-jun-NH 2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。 在心脏中，在人和动物模型中的压力超负荷或缺血/梗死诱导的心脏肥大和心力衰竭中观察到p38 MAPK的活化。在培养的心肌细胞中，p38 MAPK的激活诱导心肌细胞肥大和凋亡，并且还涉及预处理过程和缺血/再灌注损伤。越来越多的证据表明，抑制p38 MAPK能够改善缺血/再灌注损伤心脏的收缩力。 本研究的具体目标是确定p38-MAPK激活是否调节心肌细胞兴奋-收缩偶联，如果是这样，探讨可能的潜在机制。我们在单细胞水平上研究了p38-MAPK激活或抑制对心肌收缩力的可能影响，并通过在过表达p38 MAPK上游激酶激活突变体的转基因小鼠中的体内研究验证了从单个心肌细胞实验中获得的结论。此外，我们还研究了AR和p38 MAPK信号通路在调节心肌收缩力方面的潜在相互作用，以及p38激活在缺血性收缩功能障碍和心肌细胞损伤中的病理生理相关性。 我们的体内和体外研究首次证明，抑制p38 MAPK导致正性肌力作用，而增强的p38 MAPK激活抑制肌细胞收缩力并否定AR/PKA介导的正性肌力作用。此外，我们已经表明，抑制缺血诱导的细胞内酸中毒介导的p38 MAPK激活不仅保护心肌细胞免受缺血性死亡，而且逆转缺血性收缩功能障碍。这些发现揭示了p38 MAPK的一种新功能，并为更好地理解在某些病理生理条件下，如心脏缺血/再灌注损伤和慢性心力衰竭，增强的p38 MAPK信号转导和心脏收缩功能障碍的巧合提供了新的见解。

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.