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Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes

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Abstract

An elevated level of homocysteine called hyperhomocysteinemia (HHcy) is associated with pathological cardiac remodeling. Hydrogen sulfide (H2S) acts as a cardioprotective gas; however, the mechanism by which H2S mitigates homocysteine-mediated pathological remodeling in cardiomyocytes is unclear. We hypothesized that H2S ameliorates HHcy-mediated hypertrophy by inducing cardioprotective miR-133a in cardiomyocytes. To test the hypothesis, HL1 cardiomyocytes were treated with (1) plain medium (control, CT), (2) 100 µM of homocysteine (Hcy), (3) Hcy with 30 µM of H2S (Hcy + H2S), and (4) H2S for 24 h. The levels of hypertrophy markers: c-fos, atrial natriuretic peptide (ANP), and beta-myosin heavy chain (β-MHC), miR-133a, and its transcriptional inducer myosin enhancer factor-2C (MEF2C) were determined by Western blotting, RT-qPCR, and immunofluorescence. The activity of MEF2C was assessed by co-immunoprecipitation of MEF2C with histone deacetylase-1(HDAC1). Our results show that H2S ameliorates homocysteine-mediated up-regulation of c-fos, ANP, and β-MHC, and down-regulation of MEF2C and miR-133a. HHcy induces the binding of MEF2C with HDAC1, whereas H2S releases MEF2C from MEF2C–HDAC1 complex causing activation of MEF2C. These findings elicit that HHcy induces cardiac hypertrophy by promoting MEF2C–HDAC1 complex formation that inactivates MEF2C causing suppression of anti-hypertrophy miR-133a in cardiomyocytes. H2S mitigates hypertrophy by inducing miR-133a through activation of MEF2C in HHcy cardiomyocytes. To our knowledge, this is a novel mechanism of H2S-mediated activation of MEF2C and induction of miR-133a and inhibition of hypertrophy in HHcy cardiomyocytes.

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Abbreviations

HHcy:

Hyperhomocysteinemia

H2S:

Hydrogen sulfide

Hcy:

Homocysteine

ANP:

Atrial natriuretic peptide

β-MHC:

Beta-myosin heavy chain

MEF2C:

Myosin-specific enhancer factor 2C

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Acknowledgments

Financial support from National Institute of Health grants: HL-113281 and HL-116205 to Paras K. Mishra is gratefully acknowledged. We would like to thank Bryan T Hackfort, a post doctoral fellow in our laboratory, for editing the final version of the manuscript.

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Authors declare that there are no conflicts of interest.

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    Authors and Affiliations

    1. Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 668 S 41st Street, DRC1, Room 5047, Omaha, NE, 68198-5850, USA

      Varun Kesherwani, Shyam Sundar Nandi, Surender K. Sharawat, Hamid R. Shahshahan & Paras Kumar Mishra

    2. Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

      Paras Kumar Mishra

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    1. Varun Kesherwani
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    Correspondence to Paras Kumar Mishra.

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    Varun Kesherwani and Shyam Sundar Nandi contributed equally.

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    Kesherwani, V., Nandi, S.S., Sharawat, S.K. et al. Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes. Mol Cell Biochem 404, 241–250 (2015). https://doi.org/10.1007/s11010-015-2383-5

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