Characterization of cardioprotective molecular mechanism via p38MAPK and new therapy for heart failure

从心脏肥大（对生物力学应激的适应性反应）转变为心力衰竭的分子机制尚不清楚。丝裂原激活蛋白激酶 p38α 是各种细胞应激反应途径的关键组成部分。为了应对左心室压力超负荷，心脏特异性 p38a 基因敲除小鼠出现心功能障碍和心脏扩张。然而，传统的杂合 p38α 敲除小鼠表现出对缺血再灌注损伤的抵抗力。这些结果表明p38α在细胞死亡调节中发挥保护和促进作用。为了表征决定p38在细胞死亡调节中双重作用的分子机制，并获得心力衰竭的新靶点，我们在他莫昔芬诱导型和心脏特异性p38α敲除（诱导型p38αCKO）小鼠中检查了主动脉束带和异丙肾上腺素治疗。我们在TAC之前或之后进行了他莫昔芬注射。诱导型 p38αCKO 小鼠。我们还在异丙肾上腺素治疗之前或期间进行了他莫昔芬注射。然而，我们得到了与诱导型p38αCKO小鼠在所有条件下均出现心功能障碍相同的结果，因此我们无法表征本实验中决定p38在调节细胞死亡中双重作用的分子机制。我们检查了心肌细胞死亡的分子机制，并得到了结果：凋亡信号调节激酶1（ASK1）不仅参与细胞凋亡，还参与缺血再灌注引起的非凋亡心肌细胞死亡。我们综述了ASK1在心肌细胞凋亡中的作用。我们还报道，抗氧化剂依达拉奉可减轻压力超负荷引起的左心室肥大，早老素 2 通过与心脏中的心脏兰尼碱受体相互作用，在兴奋-收缩耦合中发挥重要作用。

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38α is a key component of stress response pathways in various types of cells. In response to pressure overload to the left ventricle, cardiac-specific p38a knockout mice developed cardiac dysfunction and heart dilatation. However, the conventional heterozygous p38α knockout mice exhibited resistance to ischemia-reperfusion insult. These results indicated that p38α plays a protective and promoting role in the regulation of cell death.In order to characterize the molecular mechanism which determines the dual roles of p38 in the regulation of cell death and obtain a new target for heart failure, we examined aortic banding and isoproterenol treatment in the tamoxifen-inducible and cardiac-specific p38α knockout (inducible p38αCKO) mice.We performed Tamoxifen injection before or after TAC in the inducible p38αCKO mice. We also performed Tamoxifen injection before or during treatment with isoproterenol. However, we obtained the same results that the inducible p38αCKO mice developed cardiac dysfunction in all condition, concluding that we can not characterize the molecular mechanism which determines the dual roles of p38 in the regulation of cell death in this experiment.We examined the molecular mechanism of the myocardial cell death and obtained the result that apoptosis signal-regulating kinase 1 (ASK1) is involved not only in apoptosis but also in non-apoptotic cardiomyocyte death by ischemia-reperfusion. We reviewed that the role of ASK1 in cardiomyocyte apoptosis. We also reported that the antioxidant edaravone attenuates pressure overload-induced left ventricular hypertrophy and that presenilin 2 plays an important role in excitation-contraction coupling by interacting with cardiac ryanodine receptor in hearts.