Integrated pharmacological preconditioning and memory of cardioprotection: role of protein kinase C and phosphatidylinositol 3-kinase.
Integrated pharmacological preconditioning and memory of cardioprotection: role of protein kinase C and phosphatidylinositol 3-kinase.
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DOI：
10.1152/ajpheart.00012.2005
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发表时间：
2005-04
期刊：
影响因子：
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通讯作者：
T. Okada;H. Otani;Yue Wu;Takamichi Uchiyama;S. Kyoi;R. Hattori;Tomohiko Sumida;Hiroyoshi Fujiwara;H. Imamura
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文献类型：
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作者：
T. Okada;H. Otani;Yue Wu;Takamichi Uchiyama;S. Kyoi;R. Hattori;Tomohiko Sumida;Hiroyoshi Fujiwara;H. Imamura
尽管蛋白激酶C（PKC）和磷脂酰肌醇3（PI 3）激酶参与了缺血预处理介导的心肌保护信号转导，但它们在药物预处理（PPC）中的作用尚未确定。培养的新生大鼠心肌细胞（CMC）进行模拟缺血2小时，然后复氧15分钟。CMC的PPC包括在模拟缺血之前单独或组合施用50 μ M腺苷、50 μ M二氮嗪和50 μ M S-亚硝基-N-乙酰青霉胺（SNAP）15分钟，随后冲洗30分钟。虽然PKC-β和PI 3-激酶在腺苷治疗期间被显著激活，但这些激酶的激活在洗脱后消失。相反，PPC与腺苷、二氮嗪和SNAP组合在洗脱后引起PKC-β和PI-3激酶的持续激活。联合PPC，但不是单一PPC，协议赋予抗凋亡和抗坏死作用后复氧。在洗脱期给予的PKC抑制剂白屈菜红碱（5 μ M）或PI 3-激酶抑制剂LY-294002（10 μ M）部分阻断由组合PPC方案介导的PKC-β和PI 3-激酶的活化，而白屈菜红碱和LY-294002的组合添加完全抑制PKC-β和PI 3-激酶的活化。白屈菜红碱或LY-294002部分阻断联合PPC方案介导的抗凋亡和抗坏死作用，而白屈菜红碱和LY-294002的联合添加完全废除了抗凋亡和抗坏死作用。这些结果表明，组合PPC协议赋予心脏保护记忆通过持续和相互依赖的激活PKC和PI 3-激酶。
Although protein kinase C (PKC) and phosphatidylinositol 3 (PI3)-kinase are implicated in cardioprotective signal transduction mediated by ischemic preconditioning, their role in pharmacological preconditioning (PPC) has not been determined. Cultured neonatal rat cardiomyocytes (CMCs) were subjected to simulated ischemia for 2 h followed by 15 min of reoxygenation. PPC of CMCs consisted of administration of 50 microM adenosine, 50 microM diazoxide, and 50 microM S-nitroso-N-acetylpenicillamine (SNAP), each alone or in combination, for 15 min followed by 30 min of washout before simulated ischemia. Although PKC-epsilon and PI3-kinase were significantly activated during treatment with adenosine, activation of these kinases dissipated after washout. In contrast, PPC combined with adenosine, diazoxide, and SNAP elicited sustained activation of PKC-epsilon and PI-3 kinase after washout. The combined-PPC, but not the single-PPC, protocol conferred antiapoptotic and antinecrotic effects after reoxygenation. The PKC inhibitor chelerythrine (5 microM) or the PI3-kinase inhibitor LY-294002 (10 microM) given during the washout period partially blocked the activation of PKC-epsilon and PI3-kinase mediated by the combined-PPC protocol, whereas combined addition of chelerythrine and LY-294002 completely inhibited activation of PKC-epsilon and PI3-kinase. Chelerythrine or LY-294002 partially blocked antiapoptotic and antinecrotic effects mediated by the combined-PPC protocol, whereas combined addition of chelerythrine and LY-294002 completely abrogated antiapoptotic and antinecrotic effects. These results suggest that the combined-PPC protocol confers cardioprotective memory through sustained and interdependent activation of PKC and PI3-kinase.