Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes.
High serum levels of p-cresol have been associated with cardiovascular diseases. This study investigated the effects of p-cresol on gap junctions in neonatal cultured cardiomyocytes. p-Cresol reduced the spontaneous contraction rates of cardiomyocytes, and caused irregular cardiomyocyte beating. Junctional connexin 43 (Cx43) plaques became smaller in size and the gap junction intercellular communication (GJIC) impaired. Moreover, p-cresol increased intracellular Ca(+2) levels, and induced Ca(+2)-dependent protein kinase Cα (PKCα) activation. p-Cresol decreased P1 and P2 Cx43 levels, and increased non-phosphorylated S368-Cx43 levels. The above changes as well as Cx43 disassembly and GJIC decrease induced by p-cresol were prevented by the BAPTA-AM or PKCα inhibitor Gö6976. These results suggest that PKCα mediates p-cresol-induced gap junction disassembly and GJIC dysfunction via S368-Cx43 serine dephosphorylation. This hypothesis was further confirmed in H9c2 cells by siRNA approach. SiRNA knockdown of PKCα prevented p-cresol-induced increase in nonphosphorylated Cx43. This finding supports the association of p-cresol and cardiovascular diseases.
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yu-Sen
YS
Peng
Hsiu-Chi
HC
Ding
Yen-Tung
YT
Lin
Jhih-Pu
JP
Syu
Ying
Y
Chen
Seu-Mei
SM
Wang
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D002478:Cells, Cultured; D003408:Cresols / Q000633:toxicity*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D003408:Cresols; D034741:RNA, Small Interfering; C032538:4-cresol; D051571:Protein Kinase C-alpha; D002118:Calcium