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

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• 作者：Hanqiao Zheng ; Mingxin Tang ; Qingwen Zheng ; Asangi R.K. Kumarapeli ; Kathleen M. Horak ; Zongwen Tian ; Xuejun Wang
• 关键词：α ; B-crystallin ; cardiomyopathy ; doxycycline ; protein aggregation ; ubiquitin
• 刊名：Journal of the American College of Cardiology
• 出版年：2010
• 出版时间：19 October 2010
• 年：2010
• 卷：56
• 期：17
• 页码：1418-1426
• 全文大小：2070 K

文摘

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 αB-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.