Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy

Hanqiao Zheng, Mingxin Tang, Qingwen Zheng, Asangi R K Kumarapeli, Kathleen M. Horak, Zongwen Tian, Xuejun Wang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 (CryABR120G) 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 CryABR120G TG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p < 0.01). In another cohort of CryABR120G 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 CryABR120G 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 CryABR120G expression. Conclusions Doxy suppresses CryABR120G-induced aberrant protein aggregation in cardiomyocytes and prolongs CryABR120G-based DRC mouse survival.

Original languageEnglish (US)
Pages (from-to)1418-1426
Number of pages9
JournalJournal of the American College of Cardiology
Volume56
Issue number17
DOIs
StatePublished - Oct 19 2010
Externally publishedYes

Fingerprint

Doxycycline
Cardiac Myocytes
Desmin
Cardiomyopathies
Proteins
Detergents
Transgenic Mice
Ubiquitinated Proteins
Therapeutics
Crystallins
Premature Mortality
Cardiomegaly
Missense Mutation
Adenoviridae
Drinking Water
Up-Regulation
Animal Models
Cell Culture Techniques
Placebos

Keywords

  • cardiomyopathy
  • doxycycline
  • protein aggregation
  • ubiquitin
  • αB-crystallin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy. / Zheng, Hanqiao; Tang, Mingxin; Zheng, Qingwen; Kumarapeli, Asangi R K; Horak, Kathleen M.; Tian, Zongwen; Wang, Xuejun.

In: Journal of the American College of Cardiology, Vol. 56, No. 17, 19.10.2010, p. 1418-1426.

Research output: Contribution to journalArticle

Zheng, Hanqiao ; Tang, Mingxin ; Zheng, Qingwen ; Kumarapeli, Asangi R K ; Horak, Kathleen M. ; Tian, Zongwen ; Wang, Xuejun. / Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy. In: Journal of the American College of Cardiology. 2010 ; Vol. 56, No. 17. pp. 1418-1426.
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AU - Zheng, Hanqiao

AU - Tang, Mingxin

AU - Zheng, Qingwen

AU - Kumarapeli, Asangi R K

AU - Horak, Kathleen M.

AU - Tian, Zongwen

AU - Wang, Xuejun

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N2 - 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 (CryABR120G) 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 CryABR120G TG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p < 0.01). In another cohort of CryABR120G 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 CryABR120G 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 CryABR120G expression. Conclusions Doxy suppresses CryABR120G-induced aberrant protein aggregation in cardiomyocytes and prolongs CryABR120G-based DRC mouse survival.

AB - 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 (CryABR120G) 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 CryABR120G TG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p < 0.01). In another cohort of CryABR120G 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 CryABR120G 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 CryABR120G expression. Conclusions Doxy suppresses CryABR120G-induced aberrant protein aggregation in cardiomyocytes and prolongs CryABR120G-based DRC mouse survival.

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KW - ubiquitin

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