Involvement of activated SUMO-2 conjugation in cardiomyopathy

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Kim, Eun Young¹  Zhang, Yi²  Ye, Bo³  Segura, Ana Maria⁴  Beketaev, Ilimbek¹  Xi, Yutao⁵  Yu, Wei⁶  Chang, Jiang⁷  Li, Faqian³  Wang, Jun¹ 

[1] St Lukes Episcopal Hosp, Texas Heart Inst, Dept Basic Res Labs, Ctr Stem Cell Engn, Houston, TX 77030 USA

[2] Hainan Med Univ, Affiliated Hosp, Vitro Fertilizat Ctr, Haikou 570102, Hainan, Peoples R China

[3] Univ Rochester, Med Ctr, Dept Pathol & Lab Med, Rochester, NY 14642 USA

[4] St Lukes Episcopal Hosp, Texas Heart Inst, Dept Cardiac Pathol, Houston, TX 77030 USA

[5] St Lukes Episcopal Hosp, Texas Heart Inst, Dept Basic Res Labs, Lab Electrophysiol, Houston, TX 77030 USA

[6] Univ Houston, Dept Biochem & Mol Biol, Houston, TX 77204 USA

[7] Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Ctr Mol Dev & Dis, Houston, TX 77030 USA

关键词: SUMO;    Cardiomyopathy;    Apoptosis;    Calpain 2;    Calpastatin;   

DOI  :  10.1016/j.bbadis.2015.03.013

来源: Elsevier

【 摘 要 】

Sumoylation is a posttranslational modification that regulates a wide spectrum of cellular activities. Cardiomyopathy is the leading cause of heart failure. Whether sumoylation, particularly SUMO-2/3 conjugation, is involved in cardiomyopathy has not been investigated. We report here that SUMO-2/3 conjugation was elevated in the human failing hearts, and we investigated the impact of increased SUMO-2 conjugation on heart function by using the gain-of-function approach in mice, in which cardiac specific expression of constitutively active SUMO-2 was governed by alpha myosin heavy chain promoter (MHC-SUMO-2 transgenic, SUMO-2-Tg). Four of five independent SUMO-2-Tg mouse lines exhibited cardiomyopathy with various severities, ranging from acute heart failure leading to early death to the development of chronic cardiomyopathy with aging. We further revealed that SUMO-2 directly regulated apoptotic process by at least partially targeting calpain 2 and its natural inhibitor calpastatin. SUMO conjugation to calpain 2 promoted its enzymatic activity, and SUMO attachment to calpastatin mainly promoted its turnover and altered its subcellular distribution. Thus, enhanced SUMO-2 conjugation led to increased apoptosis and played a pathogenic role in the development of cardiomyopathy and heart failure. (C) 2015 Elsevier B.V. All rights reserved.

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