Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes

• Published in: PloS one 2016-01, Vol.11 (1), p.e0145750-e0145750
• Main Authors: Joseph, Leroy C, Barca, Emanuele, Subramanyam, Prakash, Komrowski, Michael, Pajvani, Utpal, Colecraft, Henry M, Hirano, Michio, Morrow, John P
• Format: Article
• Language: English
• Subjects: Abnormalities; Animals; Antimycin A - chemistry; Antioxidants; Antioxidants - chemistry; Apoptosis; Arrhythmia; Biophysics; Calcium; Calcium (mitochondrial); Calcium (reticular); Calcium - metabolism; Calcium homeostasis; Cardiac arrhythmia; Cardiac muscle; Cardiomyocytes; Cardiovascular diseases; Cell Line; Clinical trials; Clonal deletion; Coronary artery disease; CYBB protein; Depolarization; Diabetes; Diabetes mellitus; Electron Transport; Epidemiology; Fatty acids; Gene Deletion; Health aspects; Heart; Heart cells; Heart diseases; Heart failure; Heart Ventricles - pathology; Homeostasis; Inhibition; Laboratory animals; Leak channels; Male; Medicine; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Molecular modelling; Muscle Cells - cytology; Myocytes; Myocytes, Cardiac - cytology; NAD(P)H oxidase; NADPH Oxidase 2; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; Obesity; Oxidases; Oxidative stress; Oxidative Stress - drug effects; Oxygen; Oxygen Consumption; Palmitates - adverse effects; Palmitates - chemistry; Palmitic acid; Physicians; Physiological aspects; Physiology; Prevention; Protein kinase C; Protein Kinase C - chemistry; Reactive oxygen species; Reactive Oxygen Species - chemistry; Rodents; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - metabolism; Saturated fatty acids; Signal Transduction; Studies; Surgeons; Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0145750

Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced-ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate-induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity.