The Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1 alpha-Heme Oxygenase 1 Axis, a Powerful Antioxidative Pathway with Potential to Attenuate Diabetic Cardiomyopathy

Significance: From studies of diabetic animal models, the downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha)-heme oxygenase 1 (HO-1) axis appears to be a crucial event in the development of obesity and diabetic cardiomyopathy (DCM). In this review, we discuss the role of metabolic and biochemical stressors in the rodent and human pathophysiology of DCM. A crucial contributor for many cardiac pathologies is excessive production of reactive oxygen species (ROS) pathologies, which lead to extensive cellular damage by impairing mitochondrial function and directly oxidizing DNA, proteins, and lipid membranes. We discuss the role of ROS production and inflammatory pathways with multiple contributing and confounding factors leading to DCM. Recent Advances: The relevant biochemical pathways that are critical to a therapeutic approach to treat DCM, specifically caloric restriction and its relation to the PGC-1 alpha-HO-1 axis in the attenuation of DCM, are elucidated. Critical Issues: The increased prevalence of diabetes mellitus type 2, a major contributor to unique cardiomyopathy characterized by cardiomyocyte hypertrophy with no effective clinical treatment. This review highlights the role of mitochondrial dysfunction in the development of DCM and potential oxidative targets to attenuate oxidative stress and attenuate DCM. Future Directions: Targeting the PGC-1 alpha-HO-1 axis is a promising approach to ameliorate DCM through improvement in mitochondrial function and antioxidant defenses. A pharmacological inducer to activate PGC-1 alpha and HO-1 described in this review may be a promising therapeutic approach in the clinical setting.