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Selective homocysteine-lowering gene transfer attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress

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Abstract

Plasma homocysteine levels predict heart failure incidence in prospective epidemiological studies. We evaluated whether selective homocysteine-lowering gene transfer beneficially affects cardiac remodeling and function in a model of pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC). Female C57BL/6 low-density lipoprotein receptor (Ldlr −/−) cystathionine-β-synthase (Cbs +/−) mice were fed standard chow (control mice) or a folate-depleted, methionine-enriched diet to induce hyperhomocysteinemia (diet mice). Three weeks after initiation of thisdiet, mice were intravenously injected with 5 × 1010 viral particles of an E1E3E4-deleted hepatocyte-specific adenoviral vector expressing Cbs (AdCBS), with the same dose of control vector, or with saline buffer. TAC or sham operation was performed 2 weeks later. AdCBS gene transfer resulted in 86.4 % (p < 0.001) and 84.6 % (p < 0.001) lower homocysteine levels in diet sham mice and diet TAC mice, respectively. Mortality rate was significantly reduced in diet AdCBS TAC mice compared to diet TAC mice during a follow-up period of 8 weeks (hazard ratio for mortality 0.495, 95 % CI 0.249 to 0.985). Left ventricular hypertrophy (p < 0.01) and interstitial myocardial fibrosis (p < 0.001) were strikingly lower in control TAC mice and diet AdCBS TAC mice compared to diet TAC mice. Diastolic function in diet AdCBS TAC mice was similar to that of control TAC mice and was significantly improved compared to diet TACmice. AdCBS gene transfer potently reduced oxidative stress as evidenced by a reduction of plasma TBARS and a reduction of myocardial 3-nitrotyrosine-positive area (%). In conclusion, selective homocysteine lowering potently attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress.

Key message

  • Plasma homocysteine levels predict heart failure incidence in epidemiological studies.

  • Transverse aortic constriction (TAC) induces pressure overload.

  • Selective homocysteine-lowering gene therapy reduces mortality after TAC.

  • Selective homocysteine lowering attenuates cardiac hypertrophy and fibrosis after TAC.

  • Decreased homocysteine levels enhance diastolic function and lower oxidative stress.

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Acknowledgments

This work was supported by Onderzoekstoelagen grant OT/13/090 of the KU Leuven and by grant G0A3114N of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.

Conflict of interest

None of the authors has a conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Institutional Animal Care and Research Advisory Committee of the Catholic University of Leuven; approval number P154/2013).

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Authors and Affiliations

  1. Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, Campus Gasthuisberg, Herestraat 49 bus 911, 3000, Leuven, Belgium

    Ilayaraja Muthuramu, Neha Singh, Ruhul Amin, Elena Nefyodova, Mirjam Debasse, Isa Van Horenbeeck, Frank Jacobs & Bart De Geest

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  1. Ilayaraja Muthuramu
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  2. Neha Singh
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Correspondence to Bart De Geest.

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Muthuramu, I., Singh, N., Amin, R. et al. Selective homocysteine-lowering gene transfer attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress. J Mol Med 93, 609–618 (2015). https://doi.org/10.1007/s00109-015-1281-3

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