Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy

• Published in: Free radical biology & medicine 2015-10, Vol.87, p.263-273
• Main Authors: Umbarkar, Prachi, Singh, Sarojini, Arkat, Silpa, Bodhankar, S.L., Lohidasan, Sathiyanarayanan, Sitasawad, Sandhya L.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Cardiac dysfunction; Clorgyline - administration & dosage; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetic Cardiomyopathies - genetics; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - pathology; Diabetic cardiomyopathy; Fibrosis - genetics; Fibrosis - metabolism; Fibrosis - pathology; Free radicals; Humans; Lipid Peroxidation - genetics; Monoamine Oxidase - drug effects; Monoamine Oxidase - metabolism; Monoamine oxidase A; Monoamine Oxidase Inhibitors - administration & dosage; Myocardial Contraction - drug effects; Myocardium - metabolism; Myocardium - pathology; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Rats; Reactive Oxygen Species - metabolism; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - pathology
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.06.025

Oxidative stress is closely associated with the pathophysiology of diabetic cardiomyopathy (DCM). The mitochondrial flavoenzyme monoamine oxidase A (MAO-A) is an important source of oxidative stress in the myocardium. We sought to determine whether MAO-A plays a major role in modulating DCM. Diabetes was induced in Wistar rats by single intraperitoneal injection of streptozotocin (STZ). To investigate the role of MAO-A in the development of pathophysiological features of DCM, hyperglycemic and age-matched control rats were treated with or without the MAO-A-specific inhibitor clorgyline (CLG) at 1mg/kg/day for 8 weeks. Diabetes upregulated MAO-A activity; elevated markers of oxidative stress such as cardiac lipid peroxidation, superoxide dismutase activity, and UCP3 protein expression; enhanced apoptotic cell death; and increased fibrosis. All these parameters were significantly attenuated by CLG treatment. In addition, treatment with CLG substantially prevented diabetes-induced cardiac contractile dysfunction as evidenced by decreased QRS, QT, and corrected QT intervals, measured by ECG, and LV systolic and LV end-diastolic pressure measured by microtip pressure transducer. These beneficial effects of CLG were seen despite the persistent hyperglycemic and hyperlipidemic environments in STZ-induced experimental diabetes. In summary, this study provides strong evidence that MAO-A is an important source of oxidative stress in the heart and that MAO-A-derived reactive oxygen species contribute to DCM. [Display omitted]