Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and εPKC
Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and εPKC
复制标题
DOI：
10.1073/pnas.191369098
复制
发表时间：
2001-09-25
影响因子：
11.1
通讯作者：
Mochly-Rosen, D
中科院分区：
文献类型：
--
作者：
Chen, L;Hahn, H;Mochly-Rosen, D
蛋白激酶C （PKC）同工酶在心脏病中的相互矛盾的作用已被报道。在分子建模和结构同源性分析的基础上，合理设计了pkc选择性激活肽和抑制肽。与先前鉴定的epsilon PKC激活肽和抑制剂肽一起，PKC δ肽被用来鉴定这些同工酶的心脏功能。在离体心肌细胞、灌注心脏和转基因小鼠中，delta PKC和epsilon PKC对缺血诱导损伤的保护作用相反。具体来说，epsilon PKC的激活引起心脏保护，而delta PKC的激活增加了体外和体内缺血引起的损伤。相反，delta PKC和epsilon PKC引起相同的非病理性心肌肥大；两种同工酶的激活均引起非病理性心脏肥大。这些结果表明，两种相关的PKC同工酶在心脏中具有平行和相反的作用，表明使用非选择性同工酶抑制剂和激活剂的治疗方法存在危险。此外，通过冠状动脉灌注PKC的选择性调节肽来减少缺血引起的心脏损伤是开发急性心脏缺血治疗剂的重要一步。
Conflicting roles for protein kinase C (PKC) isozymes in cardiac disease have been reported. Here, delta PKC-selective activator and inhibitor peptides were designed rationally, based on molecular modeling and structural homology analyses. Together with previously identified activator and inhibitor peptides of epsilon PKC, delta PKC peptides were used to identify cardiac functions of these isozymes. In isolated cardiomyocytes, perfused hearts, and transgenic mice, delta PKC and epsilon PKC had opposing actions on protection from ischemia-induced damage. Specifically, activation of epsilon PKC caused cardioprotection whereas activation of delta PKC increased damage induced by ischemia in vitro and in vivo. In contrast, delta PKC and epsilon PKC caused identical nonpathological cardiac hypertrophy; activation of either isozyme caused nonpathological hypertrophy of the heart. These results demonstrate that two related PKC isozymes have both parallel and opposing effects in the heart, indicating the danger in the use of therapeutics with nonselective isozyme inhibitors and activators. Moreover, reduction in cardiac damage caused by ischemia by perfusion of selective regulator peptides of PKC through the coronary arteries constitutes a major step toward developing a therapeutic agent for acute cardiac ischemia.