Protein kinase C-Fyn kinase cascade mediates the oleic acid-induced disassembly of neonatal rat cardiomyocyte adherens junctions.
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)-alpha and -epsilon 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 Gö6976 (a PKCalpha inhibitor), epsilonV1-2 (a PKCepsilon inhibitor), or PP2 (a Src family kinase inhibitor). Src family kinase appeared to be the downstream of PKC-alpha and -epsilon, as blockade of either PKC-alpha or -epsilon 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/beta-catenin with Fyn and Fer and caused increased tyrosine phosphorylation of p120 catenin and beta-catenin, resulting in decreased binding of the former to N-cadherin and of the latter to alpha-catenin. Pretreatment with PP2 abrogated this OA-induced tyrosine phosphorylation of p120 catenin and beta-catenin and restored the association of N-cadherin with p120 catenin and that of beta-catenin with alpha-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-alpha/-epsilon and Src family kinase are potential candidates as cardioprotection agents against OA-induced heart injury during ischemia-reperfusion.
Hsu
Kwan-Lih
KL
Department of Internal Medicine, E-Da Hospital, Department of Nursing, I-Shou University, Kaohsiung, Taiwan.
Fan
Han-Jou
HJ
Chen
Yung-Chia
YC
Huang
Yuahn-Sieh
YS
Chen
Chia-Huei
CH
Wu
Jiahn-Chun
JC
Wang
Seu-Mei
SM
D022005:Adherens Junctions / Q000187:drug effects* / Q000201:enzymology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009336:Necrosis / Q000201:enzymology; D019301:Oleic Acid / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000095002:Delta Catenin
D051177:Catenins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D019000:Phosphotyrosine; D019301:Oleic Acid; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D000095002:Delta Catenin; C000722355:Ctnnd1 protein, rat