Peritoneal dialysate effluent during peritonitis induces human cardiomyocyte apoptosis by regulating the expression of GATA-4 and Bcl-2 families.
Cardiovascular event and infection are leading causes of death from peritoneal dialysis (PD). This study examined in vitro cellular mechanism for cardiotoxicity induced by PD-related peritonitis. Cultured human cardiomyocytes were treated with PD effluent (PDE) during peritonitis (PPDE), and effects of PPDE on cultured cardiomyocytes in terms of apoptosis, with expression its related genes assessed. Results showed PPDE treatment of cardiomyocyte leading to onset of apoptosis, as confirmed by phosphatidylserine exposure plus DNA fragmentation and damage. This apoptosis is mediated by reduced Bcl-2/Bax and Bcl-x(L)/Bax ratios, as well as reduced expression of GATA-4, an important cardiomyocyte survival factor, at the level of transcription. These changes activated pro-apoptotic pathways. PPDE treatment also inhibited ERK signals, contributing to cardiotoxicity. Our findings revealed that PPDE contains potent pro-apoptotic factors that regulate expression of GATA-4 and Bcl-2 families, inducing cultured cardiomyocyte apoptosis. This pinpoints a key role of apoptosis in PD-associated cardiovascular events, along with a potential therapeutic target.
Wang
Hsin-Hui
HH
Department of Pediatrics, Division of Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan.
Li
Ping-Chun
PC
Huang
Hsiao-Ju
HJ
Lee
Tzong-Yann
TY
Lin
Ching-Yuang
CY
D017209:Apoptosis / Q000187:drug effects*; D001202:Ascitic Fluid / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D010530:Peritoneal Dialysis; D010538:Peritonitis / Q000473:pathology / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D048049:Extracellular Signal-Regulated MAP Kinases