Doxycycline Attenuates Protein Aggregation in Cardiomyocytes and Improves Survival of a Mouse Model of Cardiac Proteinopathy

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:56

Article

Zheng, Hanqiao¹  Tang, Mingxin¹  Zheng, Qingwen¹  Kumarapeli, Asangi R. K.¹  Horak, Kathleen M.¹  Tian, Zongwen¹  Wang, Xuejun¹ 

[1] Univ S Dakota, Sanford Sch Med, Div Basic Biomed Sci, Vermillion, SD 57069 USA

关键词: alpha B-crystallin;    cardiomyopathy;    doxycycline;    protein aggregation;    ubiquitin;   

DOI  :  10.1016/j.jacc.2010.01.075

来源: Elsevier

【 摘 要 】

Objectives The goal of this pre-clinical study was to assess the therapeutic efficacy of doxycycline (Doxy) for desmin-related cardiomyopathy (DRC) and to elucidate the potential mechanisms involved. Background DRC, exemplifying cardiac proteinopathy, is characterized by intrasarcoplasmic protein aggregation and cardiac insufficiency. No effective treatment for DRC is available presently. Doxy was shown to attenuate aberrant intranuclear aggregation and toxicity of misfolded proteins in noncardiac cells and animal models of other proteinopathies. Methods Mice and cultured neonatal rat cardiomyocytes with transgenic (TG) expression of a human DRC-linked missense mutation R120G of alpha B-crystallin (CryAB(R120G)) were used for testing the effect of Doxy. Doxy was administered via drinking water (6 mg/ml) initiated at 8 or 16 weeks of age. Results Doxy treatment initiated at 16 weeks of age significantly delayed the premature death of CryAB(R120G) TG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p < 0.01). In another cohort of CryAB(R120G) TG mice, Doxy treatment initiated at 8 weeks of age significantly attenuated cardiac hypertrophy in 1 month. Further investigation revealed that Doxy significantly reduced the abundance of CryAB-positive microscopic aggregates, detergent-resistant CryAB oligomers, and total ubiquitinated proteins in CryAB(R120G) TG hearts. In cell culture, Doxy treatment dose-dependently suppressed the formation of both microscopic protein aggregates and detergent-resistant soluble CryAB(R120G) oligomers and reversed the up-regulation of p62 protein induced by adenovirus-mediated CryAB(R120G) expression. Conclusions Doxy suppresses CryAB(R120G)-induced aberrant protein aggregation in cardiomyocytes and prolongs CryAB(R120G)-based DRC mouse survival. (J Am Coll Cardiol 2010;56:1418-26) (C) 2010 by the American College of Cardiology Foundation

【 授权许可】

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