FGF-2-induced negative inotropism and cardioprotection are inhibited by chelerythrine: Involvement of sarcolemmal calcium-independent protein kinase C

Fibroblast growth factor-2 (FGF-2), administered to the isolated rat heart by perfusion and under constant pressure, is protective against ischemia-re perfusion (T-R). Here we have investigated whether FGF-2 cardioprotection: (a) is dependent on flow modulation; (b) is linked to effects on contractil ity; (c) is mediated by protein kinase C (PKC); and (d) is linked to PKC an d/or mitogen activated protein kinase (MAPK) associated with the sarcolemma . The isolated rat heart was used as a model. Under conditions of constant now FGF-2 induced significant improvement in recovery of contractile functi on during I-R, Under constant perfusion pressure, FGF-2 induced a negative inotropic effect (15% decrease in developed pressure). Chelerythrine, a spe cific PKC inhibitor, prevented both the FGF-2-induced negative inotropic ef fect before ischemia, and cardioprotection during I-R. FGF-2 induced a cher erythrine-preventable, five-fold increase in sarcolemmal calcium-independen t PKC activity, It also increased the association of PKC subtypes -epsilon and -delta with sarcolemmal membranes, detected by Western blotting, as wel l as, for PKC delta, by immunolocalization. FGF-2 increased the association of PKC epsilon with the membrane fraction of adult cardiomyocyte in cultur e, confirming that it can affect PKC signaling in cardiomyocytes directly a nd in a manner similar to its effects in situ, Finally FGF-2 induced increa sed active MAPK at sarcolemmal as well as cytosolic sites. Active sarcolemm al MAPK remained elevated when the FGF-2-induced protection was prevented b y chelerythrine. In conclusion, we have provided evidence that cardioprotec tion by FGF-2 is independent of flow modulation, PKC activation mediates bo th the FGF-2-induced negative inotropic effect before ischemia and the card ioprotective effect assessed during reperfusion, suggesting a cause and eff ect relationship. Furthermore, FGF-2 cardioprotection is linked to targetin g of sarcolemmal sites by calcium-independent PKC. (C) 1998 Academic Press.