title: Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes.
abstract: 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.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Leroy C
authors.initials: LC
authors.lastname: Joseph
authors.affiliation: Department of Neurology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Barca
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, New York, United States of America.
authors.forename: Prakash
authors.initials: P
authors.lastname: Subramanyam
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Komrowski
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Utpal
authors.initials: U
authors.lastname: Pajvani
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, New York, United States of America.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Colecraft
authors.affiliation: Department of Neurology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Morrow
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004579:Electron Transport; D017353:Gene Deletion; D006352:Heart Ventricles / Q000473:pathology; D006706:Homeostasis; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D032342:Muscle Cells / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption; D010168:Palmitates / Q000009:adverse effects* / Q000737:chemistry; D011493:Protein Kinase C / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D008562:Membrane Glycoproteins; D010168:Palmitates; D017382:Reactive Oxygen Species; D000968:Antimycin A; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011493:Protein Kinase C; D002118:Calcium