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两种不同的机制介导急性和持续性心肌缺血中蛋白激酶C同工酶的差异调节。

Two distinct mechanisms mediate a differential regulation of protein kinase C isozymes in acute and prolonged myocardial ischemia.

作者信息

Strasser R H, Simonis G, Schön S P, Braun M U, Ihl-Vahl R, Weinbrenner C, Marquetant R, Kübler W

机构信息

Department of Cardiology, Angiology, and Pulmology, University of Heidelberg, Medical Center, Heidelberg, Germany.

出版信息

Circ Res. 1999 Jul 9;85(1):77-87. doi: 10.1161/01.res.85.1.77.

Abstract

An activation of protein kinase C (PKC) in acute myocardial ischemia has been shown previously using its translocation to the plasma membrane as an indirect parameter. However, whether PKC remains activated or whether other mechanisms such as altered gene expression may mediate an isozyme-specific regulation in prolonged ischemia have not been investigated. In isolated perfused rat hearts, PKC activity and the expression of PKC cardiac isozymes were determined on the protein level using enzyme activities and Western blot analyses and on the mRNA level using reverse transcriptase-polymerase chain reaction after various periods of global ischemia (1 to 60 minutes). As early as 1 minute after the onset of ischemia, PKC activity is translocated from the cytosol to the particulate fraction without change in total cardiac enzyme activity. This translocation involves all major cardiac isozymes of PKC (ie, PKCalpha, PKCdelta, PKCepsilon, and PKCzeta). This rapid, nonselective activation of PKCs is only transient. In contrast, prolonged ischemia (>/=15 minutes) leads to an increased cardiac PKC activity (119+/-7 versus 190+/-8 pmol/min per mg protein) residing in the cytosol. This is associated with an augmented, subtype-selective isozyme expression of PKCdelta and PKCvarepsilon (163% and 199%, respectively). The specific mRNAs for PKCdelta (948+/-83 versus 1501+/-138 ag/ng total RNA, 30 minutes of ischemia) and PKCepsilon (1597+/-166 versus 2611+/-252 ag/ng total RNA) are selectively increased. PKCalpha and PKCzeta remain unaltered. In conclusion, two distinct activation and regulation processes of PKC are characterized in acute myocardial ischemia. The early, but transient, translocation involves all constitutively expressed cardiac isozymes of PKC, whereas in prolonged ischemia an increased total PKC activity is associated with an isozyme-selective induction of PKCepsilon and PKCdelta. Whether these fundamentally different activation processes interact remains to be elucidated.

摘要

先前已通过蛋白激酶C(PKC)转位至质膜这一间接参数,证实其在急性心肌缺血中被激活。然而,在长时间缺血过程中PKC是否持续激活,或者其他机制如基因表达改变是否介导同工酶特异性调节,尚未得到研究。在离体灌注大鼠心脏中,通过酶活性和蛋白质印迹分析在蛋白质水平测定PKC活性及PKC心脏同工酶的表达,并在不同时长的全心缺血(1至60分钟)后,使用逆转录聚合酶链反应在mRNA水平进行测定。早在缺血开始后1分钟,PKC活性就从胞质溶胶转位至颗粒部分,而心脏总酶活性未发生变化。这种转位涉及PKC的所有主要心脏同工酶(即PKCα、PKCδ、PKCε和PKCζ)。PKC的这种快速、非选择性激活只是短暂的。相比之下,长时间缺血(≥15分钟)会导致胞质溶胶中心脏PKC活性增加(分别为119±7与190±8 pmol/分钟/毫克蛋白质)。这与PKCδ和PKCε同工酶表达增加且具有亚型选择性相关(分别增加163%和199%)。PKCδ(缺血30分钟时,948±83与1501±138 ag/ng总RNA)和PKCε(1597±166与2611±252 ag/ng总RNA)的特异性mRNA选择性增加。PKCα和PKCζ保持不变。总之,急性心肌缺血中PKC存在两种不同的激活和调节过程。早期但短暂的转位涉及所有组成性表达的心脏PKC同工酶,而在长时间缺血中,PKC总活性增加与PKCε和PKCδ的同工酶选择性诱导相关。这些根本不同的激活过程是否相互作用仍有待阐明。

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