NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy

Abstract

Alcoholic cardiomyopathy (ACM) resulting from excess alcohol consumption is an important cause of heart failure (HF). Although it is assumed that the cardiotoxicity of the ethanol (EtOH)-metabolite acetaldehyde (ACA) is central for its development and progression, the exact mechanisms remain obscure. Murine cardiomyocytes (CMs) exposed to ACA or EtOH showed increased superoxide (O2•−) levels and decreased mitochondrial polarization, both being normalized by NADPH oxidase (NOX) inhibition. C57BL/6 mice and mice deficient for the ACA-degrading enzyme mitochondrial aldehyde dehydrogenase (ALDH-2−/−) were fed a 2% EtOH diet for 5 weeks creating an ACA-overload. 2% EtOH-fed ALDH-2−/− mice exhibited a decreased cardiac function, increased heart-to-body and lung-to-body weight ratios, increased cardiac levels of the lipid peroxidation product malondialdehyde (MDA) as well as increased NOX activity and NOX2/glycoprotein 91phox (NOX2/gp91phox) subunit expression compared to 2% EtOH-fed C57BL/6 mice. Echocardiography revealed that ALDH-2−/−/gp91phox−/− mice were protected from ACA-overload-induced HF after 5 weeks of 2% EtOH-diet, demonstrating that NOX2-derived O2•− contributes to the development of ACM. Translated to human pathophysiology, we found increased gp91phox expression in endomyocardial biopsies of ACM patients. In conclusion, ACM is promoted by ACA-driven mitochondrial dysfunction and can be improved by ablation of NOX2/gp91phox. NOX2/gp91phox therefore might be a potential pharmacological target to treat ACM.

Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: Therapeutic potential of NOX2 and p38MAPK inhibitors

“…Jia et al () demonstrated the occurrence of mitochondrial dysfunction in human ARPE19 cells exposed to 50 μM acrolein, also the depletion in mitochondrial potential was time dependent. Further, studies have shown earlier that, activation of NOX2 initiates and enhances mitochondrial and nuclear DNA damage (Brandt et al, ). Excess ROS production by NOX2 triggers the downstream P38MAPK signal which activates both apoptotic and necrotic pathways (Daiber et al, ).…”

AIN‐93 Diet as an Alternative Model to Lieber–DeCarli Diet for Alcoholic Cardiomyopathy

“…Left ventricular wall thickness, left ventricular end‐diastolic and end‐systolic volumes, left ventricular end‐diastolic and end‐systolic internal diameter, left ventricular ejection fraction, and left ventricular shortening fraction were determined. Some important parameters, including body temperature, heart rate, and anesthesia, were meticulously controlled to minimize iatrogenic effects on the murine cardiac physiology (Brandt et al., ).…”

“…Currently, feeding animals with Lieber–DeCarli alcoholic liquid diets is a classical method for creating animal models of ACM (Brandt et al., ; Lieber and DeCarli, ; Tan et al., ). Compared with drinking alcohol‐containing water or oral gavage diet, feeding animals only with Lieber–DeCarli alcoholic liquid diets may be more suitable for the evaluation of chronic alcohol exposure (Bertola et al., ; Matyas et al., ).…”

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

“…Recent studies show that ALDH-2 plays an important role in the reduction of myocardial damage during ischemia/reperfusion thereby reducing the infarct size [72] and confers cardio-protection in an experimental diabetes/myocardial infarction model [73]. ALDH-2 deficiency was associated with increased ROS formation in aging animals [74], alcohol-induced heart failure [75] and acetaldehyde overload as well as nitroglycerin challenges [76]. In the setting of nitroglycerin-induced nitrate tolerance oxidatively triggered proteasomal degradation of ALDH-2 protein was reported [77].…”