Protein kinase C-Fyn kinase cascade mediates the oleic acid-induced disassembly of neonatal rat cardiomyocyte adherens junctions.

Abstract Oleic acid (OA) affects assembly of gap junctions in neonatal cardiomyocytes. Adherens junction (AJ) regulates the stability of gap junction integrity; however, the effect of OA on AJ remains largely unexplored. The distribution of N-cadherin and catenins at cell–cell junction was decreased by OA. OA induced activation of protein kinase C(PKC)-α and -ɛ and Src family kinase, and all three kinases were involved in the oleic acid-induced disassembly of the adherens junction, since it was blocked by pretreatment with Go6976 (a PKCα inhibitor), ɛV1–2 (a PKCɛ inhibitor), or PP2 (a Src family kinase inhibitor). Src family kinase appeared to be the downstream of PKC-α and -ɛ, as blockade of either PKC-α or -ɛ activity prevented the OA-induced activation of Src family kinase. Immunoprecipitation analyses showed that OA activated Fyn and Fer. OA promoted the association of p120 catenin/β-catenin with Fyn and Fer and caused increased tyrosine phosphorylation of p120 catenin and β-catenin, resulting in decreased binding of the former to N-cadherin and of the latter to α-catenin. Pretreatment with PP2 abrogated this OA-induced tyrosine phosphorylation of p120 catenin and β-catenin and restored the association of N-cadherin with p120 catenin and that of β-catenin with α-catenin. In conclusion, these results show that OA activates the PKC-Fyn signaling pathway, leading to the disassembly of the AJ. Therefore, inhibitors of PKC-α/-ɛ and Src family kinase are potential candidates as cardioprotection agents against OA-induced heart injury during ischemia-reperfusion.