Two Distinct Mechanisms Mediate a Differential Regulation of Protein Kinase C Isozymes in Acute and Prolonged Myocardial Ischemia

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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, PKCα, PKCδ, PKCε, and PKCζ). 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 PKCδ and PKCε (163% and 199%, respectively). The specific mRNAs for PKCδ (948±83 versus 1501±138 ag/ng total RNA, 30 minutes of ischemia) and PKCε (1597±166 versus 2611±252 ag/ng total RNA) are selectively increased. PKCα and PKCζ 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 PKCε and PKCδ. Whether these fundamentally different activation processes interact remains to be elucidated.

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