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Published on: November 7, 2017
Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes
Yu-Sen Peng1, Hsiu-Chi Ding, Yen-Tung Lin
1Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Insights
High p-cresol levels disrupt heart cell communication, leading to irregular beating and potential cardiovascular disease. This occurs via protein kinase C alpha (PKCα) and connexin 43 (Cx43) pathways.
Area of Science:
- Cardiovascular Science
- Cell Biology
- Toxicology
Background:
- Elevated serum p-cresol is linked to cardiovascular diseases.
- Understanding p-cresol's cellular mechanisms is crucial for disease prevention.
Purpose of the Study:
- To investigate the impact of p-cresol on gap junctions in cardiomyocytes.
- To elucidate the molecular pathways involved in p-cresol-induced cardiac dysfunction.
Main Methods:
- Neonatal rat cardiomyocytes and H9c2 cells were cultured.
- Effects of p-cresol on cell contraction, connexin 43 (Cx43) localization, and gap junction intercellular communication (GJIC) were assessed.
- Intracellular calcium levels, protein kinase C alpha (PKCα) activation, and Cx43 phosphorylation status were analyzed.
- Pharmacological inhibitors (BAPTA-AM, Gö6976) and siRNA knockdown of PKCα were employed.
Main Results:
- p-Cresol reduced cardiomyocyte contraction rate and induced irregular beating.
- It decreased junctional Cx43 plaque size, impaired GJIC, and increased intracellular calcium.
- p-Cresol activated PKCα and altered Cx43 phosphorylation at S368.
- Inhibition of PKCα or calcium signaling prevented these detrimental effects.
Conclusions:
- p-Cresol induces cardiac gap junction dysfunction and GJIC impairment.
- PKCα activation, mediated by increased intracellular calcium, plays a key role in p-cresol toxicity.
- PKCα mediates p-cresol-induced Cx43 disassembly via S368 serine dephosphorylation, supporting the link between p-cresol and cardiovascular disease.
Abstract:
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.
