Down-regulation of catalase and oxidative modification of protein kinase CK2 lead to the failure of apoptosis repressor with caspase recruitment domain to inhibit cardiomyocyte hypertrophy.
Cardiac hypertrophy is regulated by a complex interplay of pro- and anti-hypertrophic factors. Here, we report a novel anti-hypertrophic pathway composed of catalase, protein kinase CK2 (CK2), and apoptosis repressor with caspase recruitment domain (ARC). Our results showed that ARC phosphorylation levels, CK2 activity, and catalase expression levels were decreased in the hearts of the angiotensinogen transgenic mice and in cardiomyocytes treated with the hypertrophic stimuli, including phenylephrine, tumor necrosis factor-alpha, and angiotensin II. To understand the role of ARC in hypertrophy, we observed that enforced expression of ARC could inhibit hypertrophy. Knockdown of endogenous ARC or inhibition of its phosphorylation could sensitize cardiomyocytes to undergoing hypertrophy. The phosphorylatable, but not the nonphosphorylatable, ARC could inhibit hypertrophy. Thus, ARC is able to inhibit hypertrophy in a phosphorylation-dependent manner. In exploring the molecular mechanism by which CK2 activity is reduced, we found that CK2 was carbonylated in angiotensinogen transgenic mice and in cardiomyocytes treated with the hypertrophic stimuli. The decrease in catalase expression led to an elevated level of reactive oxygen species. The latter oxidatively modified CK2, resulting in its carbonylation. CK2 lost its catalytic activity upon carbonylation. ARC is phosphorylated by CK2, and ARC phosphorylation levels were reduced as a consequence of the decrease of CK2 activity. To understand the molecular mechanism by which ARC inhibits hypertrophy, we observed that ARC could inhibit the activation of mitochondrial permeability transition. These results suggest that catalase, CK2, and ARC constitute an anti-hypertrophic pathway in the heart.
Murtaza
Iram
I
Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Wang
Hong-Xia
HX
Feng
Xue
X
Alenina
Natalia
N
Bader
Michael
M
Prabhakar
Bellur S
BS
Li
Pei-Feng
PF
D000804:Angiotensin II / Q000633:toxicity; D000808:Angiotensinogen / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000633:toxicity; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D002374:Catalase / Q000096:biosynthesis* / Q000235:genetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006984:Hypertrophy / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010656:Phenylephrine / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D009124:Muscle Proteins; C112246:NOL3 protein, human; C491787:Nol3 protein, mouse; C491788:Nol3 protein, rat; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000808:Angiotensinogen; D000804:Angiotensin II; D010656:Phenylephrine; D002374:Catalase; D047390:Casein Kinase II