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Functional analysis of atypical OKC and ASIP in cardiovascular diseases

非典型OKC和ASIP在心血管疾病中的功能分析

基本信息

批准号：
13670733
负责人：
UMEMURA Satoshi
金额：
$ 2.37万
依托单位：
Yokohama City University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670733/
关键词：
PKC atypical PKC ASIP Signal Transduction Hypertrophy Heart Failure Growth Factor Cardiomyocyte

项目摘要

Protein Kinase C (PKC) signaling pathway is involved in a variety of biological functions. Since activation of PKC pathway has been implicated in the development of cardiomyocyte hypertrophy, inhibition of this pathway would be an attractive target for the suppression of cardiomyocyte hypertrophy. Previous reports suggest that conventional PKC and novel PKC cause hypertrophic responses. We have recently focused our studies of PKC on atypical PKC, the third class of PKC family which is TPA and Ca2+insensitive and atypical PKC specific interacting protein (ASIP).EGF are known to induce hypertrophic responses in cardiomyocytes, and by utilizing two PKC inhibitors showing species-dependent specificity, we suggested the possible involvement of atypical PKC in EGF signaling in the heart. We examined the cardiac expression of individual PKC isoforms at the cardiac hypertrophy stage and the heart failure stage in Dahl salt-sensitive rats by Western blot analysis. The *xpressions of PKCα, β and δ increased at the cardiac hypertrophy stage and remained the elevated at the heart failure stage. On the other hand, the expression of PKC_ε and aPKCs increased at the cardiac hypertrophy stage, but this increase tended to decline at the congestive heart failure stage. These results suggest that there are two groups of PKC isoforms. Several reports suggest that PKC_α, β and δ are involved in the development of cardiac hypertrophy and heart failure and that PKC_ε plays a role in the physiological hypertrophic response and cardioprotective actions.These facts might indicate that all PKC isoforms (PKCα, β, δ, ε and aPKCs) expressed in the heart had similar function at the cardiac hypertrophy stage but two groups of PKC isoforms (PKCα, β, δand PKC_ε, aPKCs) had different function at the congestive heart failure stage.

蛋白激酶C（PKC）信号通路参与多种生物学功能。由于PKC通路的激活参与了心肌细胞肥大的发生，因此抑制该通路将是抑制心肌细胞肥大的一个有吸引力的靶点。以往的研究表明，传统的PKC和新的PKC引起肥大反应。非典型PKC是PKC家族的第三类成员，是TPA和Ca ~（2+）不敏感的非典型PKC特异性相互作用蛋白（ASIP）。EGF可诱导心肌细胞肥大，我们利用两种具有种属特异性的PKC抑制剂，推测非典型PKC可能参与EGF信号转导。我们通过Western印迹分析检测了Dahl盐敏感大鼠心肌肥厚阶段和心力衰竭阶段单个PKC亚型的心脏表达。PKCα、β和δ的表达在心肌肥厚期增加，在心力衰竭期仍保持升高趋势。PKC ε和aPKC在心肌肥厚期表达增加，但在充血性心力衰竭期表达减少。这些结果表明，有两组PKC亚型。近年来的研究表明，PKC_α、PKC_β和PKC_δ参与了心肌肥厚和心力衰竭的发生，PKC_ε参与了生理性心肌肥厚反应和心肌保护作用，提示PKC_α、PKC_β和PKC_δ均参与了心肌肥厚和心力衰竭的发生、发展和心肌保护作用。在心肌肥厚阶段，心肌组织中表达的PKCα、β、δ、ε和aPKC功能相似，但两组PKC亚型在心肌肥厚阶段的表达差异不显著。PKCα、β、δ和PKC ε、aPKC在心力衰竭阶段的作用不同。