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

p38MAPK 心脏保护分子机制的表征和心力衰竭的新疗法

基本信息

批准号：
17590732
负责人：
NISHIDA Kazuhiko
金额：
$ 1.92万
依托单位：
OSAKA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590732/
关键词：
Cardioprotection p38 MAP Kinase Heart Failure

项目摘要

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.

从心肌肥厚（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知之甚少。丝裂原活化蛋白激酶p38α是各种类型细胞应激反应途径的关键组分。为了响应左心室的压力超负荷，心脏特异性p38 a敲除小鼠发生心脏功能障碍和心脏扩张。然而，常规的杂合p38α基因敲除小鼠表现出对缺血再灌注损伤的抵抗。这些结果表明p38α在细胞死亡的调节中起保护和促进作用，为了阐明p38 α在细胞死亡调节中双重作用的分子机制，获得治疗心力衰竭的新靶点，我们检查了他莫昔芬诱导和心脏特异性p38α敲除中的主动脉结扎和异丙肾上腺素治疗在诱导型p38 α CKO小鼠中，我们在TAC之前或之后进行他莫昔芬注射。我们也在异丙肾上腺素治疗前或治疗期间进行了他莫昔芬注射。然而，我们获得了相同的结果，即诱导型p38αCKO小鼠在所有条件下均发生心功能障碍，结论：本实验尚不能确定p38在细胞死亡调控中的双重作用的分子机制，我们对心肌细胞死亡的分子机制进行了研究，发现凋亡信号调节激酶1（ASK 1）不仅参与细胞凋亡，而且参与缺血-再灌注引起的非凋亡性心肌细胞死亡。本文就ASK 1在心肌细胞凋亡中的作用作一综述。我们还报道了抗氧化剂依达拉奉减轻压力超负荷诱导的左心室肥大，早老素2通过与心脏ryanodine受体相互作用在兴奋-收缩偶联中起重要作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling

DOI：
10.1096/fj.05-3744fje
发表时间：
2005-12
期刊：
The FASEB Journal
影响因子：
0
作者：
Toshihiro Takeda;M. Asahi;O. Yamaguchi;S. Hikoso;H. Nakayama;Y. Kusakari;M. Kawai;K. Hongo;
通讯作者：
Toshihiro Takeda;M. Asahi;O. Yamaguchi;S. Hikoso;H. Nakayama;Y. Kusakari;M. Kawai;K. Hongo;

Apoptosis signal-regulating kinase 1 is involved not only in apoptosis but also in non-apoptotic cardiomyocyte death