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.

Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes

“…Our data indicate that MAOs are responsible for the oxidative stress, ER stress and fibrosis underlying cardiac dysfunction in T1D. Another study identified MAO-A as an important source of ROS in STZ-treated rats, suggesting that its inhibition may improve cardiac contractility 15. These Authors focused on the later stages of DCM, characterized by reduced heart rate and contractility, and likely associated with reduced ejection fraction and dilation.…”

“…More recently, monoamine oxidases (MAOs) have been shown to play a major role in the oxidative stress and development of several cardiovascular pathologies, including DCM 12–15. These flavoenzymes, localized at the outer mitochondrial membrane, exist as two isoenzymes (MAO-A and -B) and present unique features among ROS sources.…”

Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution

“…The outer mitochondrial membrane serotonin-degrading enzyme MAO-A is another important source of H 2 O 2 in the heart. MAO-A shows greater activity in diabetic cardiomyocytes, and MAO-A inhibition results in improved contractile function in preclinical DM models, despite persistent hyperglycemia and hyperlipidemia (71). However, no difference in MAO expression or MAO-related oxidative stress was recently observed in right atrial appendages from cardiac surgery patients with or without DM (72).…”

Naringin protects cardiomyocytes against hyperglycemia-induced injuries in vitro and in vivo

“…DCM is different from hypertensive cardiomyopathy and is a unique cardiovascular disease due to hyperglycemia-induced oxidative stress (Privratsky et al 2003, Kamalakkannan & Prince 2006, Saandeep et al 2009, Murali et al 2013, Peake et al 2013, Umbarkar et al 2015, inflammation (Marfella et al 2003, Di et al 2005, Venkatachalam et al 2008, cardiac fibrosis (Fonarow & Srikanthan 2006), myocardial apoptosis (Fonarow & Srikanthan 2006) and mitochondrial damage (Boudina et al 2007, Ceriello 2008.…”