title: Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy.
abstract: 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 1 mg/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.
authors.affiliation: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Prachi
authors.initials: P
authors.lastname: Umbarkar
authors.affiliation: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Sarojini
authors.initials: S
authors.lastname: Singh
authors.affiliation: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Silpa
authors.initials: S
authors.lastname: Arkat
authors.affiliation: Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, India.
authors.forename: S L
authors.initials: SL
authors.lastname: Bodhankar
authors.affiliation: Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, India.
authors.forename: Sathiyanarayanan
authors.initials: S
authors.lastname: Lohidasan
authors.affiliation: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India. Electronic address: ssitaswad@nccs.res.in.
authors.forename: Sandhya L
authors.initials: SL
authors.lastname: Sitasawad
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D003010:Clorgyline / Q000008:administration & dosage; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000473:pathology
chemical_list: D000975:Antioxidants; D008996:Monoamine Oxidase Inhibitors; D017382:Reactive Oxygen Species; D008995:Monoamine Oxidase; D003010:Clorgyline
keywords: Apoptosis; Cardiac dysfunction; Diabetic cardiomyopathy; Free radicals; Monoamine oxidase A; Oxidative stress