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

Leroy C Joseph,Henry M Colecraft,Michael Komrowski,Utpal Pajvani,Emanuele Barca,Michio Hirano,Prakash Subramanyam,John P Morrow,M.Faadiel Essop

doi:10.1371/journal.pone.0145750

Leroy C Joseph, Henry M Colecraft + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0145750

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Journal: PloS one	Publication Date: Jan 12, 2016
Citations: 127	License type: CC BY 4.0

Affiliation: Columbia University

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.

Highlights

Excessive lipid accumulation is found in cardiomyocytes from obese and diabetic patients, and is believed to contribute to heart failure and arrhythmia [1,2,3,4]
Palmitate causes mitochondrial reactive oxygen species (ROS) that is amplified by PKC-NOX2 activation, leading to abnormal calcium homeostasis (Fig 8)
By using pharmacologic inhibition of NOX2 and cardiomyocytes from NOX2 KO mice, we show that NOX2 has a central role in the generation of ROS caused by saturated fat

Summary

Introduction

Excessive lipid accumulation is found in cardiomyocytes from obese and diabetic patients, and is believed to contribute to heart failure and arrhythmia [1,2,3,4]. Several epidemiologic studies have shown that obese patients have approximately twice the risk of sudden cardiac death, and diabetics three times the risk, as age matched controls [10,11,12,13]. Human epidemiology studies show that higher saturated fat intake leads to an increased risk of sudden cardiac death, [14,15,16,17], suggesting that the effects of saturated fat on the heart may be more important than obesity per se. There is relatively little data regarding the effects of fatty acid metabolism on ROS and mitochondrial function in intact cardiomyocytes. We hypothesized that physiologic levels of saturated fatty acid could increase mitochondrial ROS in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function

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Discussion