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Conundrum of pathogenesis of diabetic cardiomyopathy: role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria

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Abstract

Diabetic cardiomyopathy and heart failure have been recognized as the leading causes of mortality among diabetics. Diabetic cardiomyopathy has been characterized primarily by the manifestation of left ventricular dysfunction that is independent of coronary artery disease and hypertension among the patients affected by diabetes mellitus. A complex array of contributing factors including the hypertrophy of left ventricle, alterations of metabolism, microvascular pathology, insulin resistance, fibrosis, apoptotic cell death, and oxidative stress have been implicated in the pathogenesis of diabetic cardiomyopathy. Nevertheless, the exact mechanisms underlying the pathogenesis of diabetic cardiomyopathy are yet to be established. The critical involvement of multifarious factors including the vascular endothelial dysfunction, microangiopathy, reactive oxygen species (ROS), oxidative stress, mitochondrial dysfunction has been identified in the mechanism of pathogenesis of diabetic cardiomyopathy. Although it is difficult to establish how each factor contributes to disease, the involvement of ROS and mitochondrial dysfunction are emerging as front-runners in the mechanism of pathogenesis of diabetic cardiomyopathy. This review highlights the role of vascular endothelial dysfunction, ROS, oxidative stress, and mitochondriopathy in the pathogenesis of diabetic cardiomyopathy. Furthermore, the review emphasizes that the puzzle has to be solved to firmly establish the mitochondrial and/or ROS mechanism(s) by identifying their most critical molecular players involved at both spatial and temporal levels in diabetic cardiomyopathy as targets for specific and effective pharmacological/therapeutic interventions.

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Acknowledgments

This study was supported by National Institute of Health Grants HL-56803 and HL-69910 to NM. We would like to acknowledge Shereen Cynthia D’Cruz, Ph.D and Joshua Goldman for their assistance during the preparation of the manuscript.

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Authors and Affiliations

  1. Department of Surgery, University of Connecticut Health Center, Farmington Avenue, Farmington, CT, 06032, USA

    Mandip Joshi, Vaithinathan Selvaraju, David W. McFadden & Nilanjana Maulik

  2. Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA

    Sainath R. Kotha, Smitha Malireddy & Narasimham L. Parinandi

  3. Department of Surgery, Saint Mary’s Hospital, Waterbury, CT, USA

    Mandip Joshi & Alexender Palesty

  4. Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA

    Abhay R. Satoskar

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  1. Mandip Joshi
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Joshi, M., Kotha, S.R., Malireddy, S. et al. Conundrum of pathogenesis of diabetic cardiomyopathy: role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria. Mol Cell Biochem 386, 233–249 (2014). https://doi.org/10.1007/s11010-013-1861-x

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