Interplay of Phosphorylated Apoptosis Repressor with CARD, Casein Kinase-2 and Reactive Oxygen Species in Regulating Endothelin-1-Induced Cardiomyocyte Hypertrophy.

Abstract

OBJECTIVE(S):

The role of the Apoptosis repressor with caspase recruitment domain (ARC) in apoptosis and in certain hypertrophic responses has been previously investigated, but its regulation of Endothelin-1 induced cardiac hypertrophy remains unknown. The present study discusses the inhibitory role of ARC against endothelin-induced hypertrophy.

RESULTS:

In present study Endothelin treated cardiomyocytes were used as a hypertrophic model, that were subsequently treated with adenovirus ARC and its mutant at different multiplicity of infections. Casein-kinase-2 inhibitors were used to produce dephosphorylated ARC and to study its effect on hypertrophy. Hypertrophy was assessed by cell surface area measurement, Atrial-natriuretic-Factor mRNA analysis and total protein assay. Reactive oxygen species analysis was carried out using the dichlorofluorescin-diacetate (DCFH-DA) assay. Over expression of ARC significantly inhibits Endothelin-induced cardiomyocyte hypertrophy. The nonphosphorylated mutant ARC (T149 A) remained unable to control endothelin-induced hypertrophy, suggesting a vital role for ARC phosphorylation in regulation of its activity. Sensitization study has been carried out to check the role of endogenous ARC using casein-kinase inhibitors. Finally, the significant role of ARC in regulating reactive oxygen species -mediated control of endothelin induced hypertrophy has also been assessed. Conclusion : Conclusively, present study showed the vital and potential therapeutic interventional role of ARC in preventing endothelin-1-induced cardiomyocyte hypertrophy. The regulation of hypertrophic pathway by ARC relies on blunting the reactive oxygen species attack. This study further suggests a mediatory role of casein-kinase-2 in Endothelin-induced hypertrophy, mainly through its phosphorylation of ARC.

• Authors: Iram Murtaza, Hong-Xia Wang, Sobia Mushtaq, Qamar Javed, Pei-Feng Li
• Journal: Iranian journal of basic medical sciences (Iran J Basic Med Sci) Vol. 16 Issue 8 Pg. 928-35 (Aug 2013) ISSN: 2008-3866 [Print] Iran
• PMID: 24106598 (Publication Type: Journal Article)