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Upregulation of microRNA-532 enhances cardiomyocyte apoptosis in the diabetic heart

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Abstract

Type 2 diabetes has a strong association with the development of cardiovascular disease, which is grouped as diabetic heart disease (DHD). DHD is associated with the progressive loss of cardiovascular cells through the alteration of molecular signalling pathways associated with cell death. In this study, we sought to determine whether diabetes induces dysregulation of miR-532 and if this is associated with accentuated apoptosis. RT-PCR analysis showed a significant increase in miR-532 expression in the right atrial appendage tissue of type 2 diabetic patients undergoing coronary artery bypass graft surgery. This was associated with marked downregulation of its anti-apoptotic target protein apoptosis repressor with caspase recruitment domain (ARC) and increased TUNEL positive cardiomyocytes. Further analysis showed a positive correlation between apoptosis and miR-532 levels. Time-course experiments in a mouse model of type 2 diabetes showed that diabetes-induced activation of miR-532 occurs in the later stage of the disease. Importantly, the upregulation of miR-532 preceded the activation of pro-apoptotic caspase-3/7 activity. Finally, inhibition of miR-532 activity in high glucose cultured human cardiomyocytes prevented the downregulation of ARC and attenuated apoptotic cell death. Diabetes induced activation of miR-532 plays a critical role in accelerating cardiomyocytes apoptosis. Therefore, miR-532 may serve as a promising therapeutic agent to overcome the diabetes-induced loss of cardiomyocytes.

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Funding

This study was supported by the Royal Society of New Zealand Catalyst Seed Funding (18-UOO-011-CSG), Otago School of Medical Sciences Dean’s Bequest funding; Lottery Health Board Grant (LHR‐2017‐ 46886) and University of Otago Research Grant.

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Author notes

  1. Joshua P. H. Neale

    Present address: Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, Sydney, Australia

  2. Shruti Rawal

    Present address: Harvard Medical School, 330 Brookline Ave, Boston, 02215, MA, USA

Authors and Affiliations

  1. Department of Physiology-HeartOtago, School of Biomedical Sciences, University of Otago, 270, Great King Street, Dunedin, 9016, New Zealand

    Dhananjie N. K. Chandrasekera, Joshua P. H. Neale, Isabelle van Hout, Shruti Rawal & Rajesh Katare

  2. Department of Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Gregory T. Jones

  3. Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Sean Coffey, Patrick Manning & Michael J. A. Williams

  4. Department of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Richard Bunton, Ramanen Sugunesegran, Dominic Parry & Philip Davis

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  1. Dhananjie N. K. Chandrasekera
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Chandrasekera, D.N.K., Neale, J.P.H., van Hout, I. et al. Upregulation of microRNA-532 enhances cardiomyocyte apoptosis in the diabetic heart. Apoptosis 25, 388–399 (2020). https://doi.org/10.1007/s10495-020-01609-1

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