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Title: Loss of NHE1 activity leads to reduced oxidative stress in heart and mitigates high-fat diet-induced myocardial stress.

Authors: Prasad, Vikram; Lorenz, John N; Miller, Marian L; Vairamani, Kanimozhi; Nieman, Michelle L; Wang, Yigang; Shull, Gary E

Published In J Mol Cell Cardiol, (2013 Dec)

Abstract: Acute inhibition of the NHE1 Na(+)/H(+) exchanger protects against ischemia-reperfusion injury and chronic inhibition attenuates development of cardiac hypertrophy and failure. To determine the cardiac effects of chronic inhibition of NHE1 under non-pathological conditions we used NHE1-null mice as a model of long-term NHE1 inhibition. Cardiovascular performance was relatively normal in Nhe1(-/-) mice although cardiac contractility and relaxation were slightly improved in mutant mice of the FVB/N background. GSH levels and GSH:GSSG ratios were elevated in Nhe1(-/-) hearts indicating an enhanced redox potential. Consistent with a reduced need for antioxidant protection, expression of heat shock proteins Hsp60 and Hsp25 was lower in Nhe1(-/-) hearts. Similarly, expression of mitochondrial superoxide dismutase 2 was reduced, with no increase in expression of other ROS scavenging enzymes. GLUT1 levels were increased in Nhe1(-/-) hearts, the number of lipid droplets in myocytes was reduced, and PDK4 expression was refractory to high-fat diet-induced upregulation observed in wild-type hearts. High-fat diet-induced stress was attenuated in Nhe1(-/-) hearts, as indicated by smaller increases in phosphorylation of Hsp25 and α-B crystallin, and there was better preservation of insulin sensitivity, as evidenced by PKB/Akt phosphorylation. Plasma glucose and insulin levels were lower and high-fat diet-induced hepatic lipid accumulation was reduced in Nhe1(-/-) mice, demonstrating extracardiac effects of NHE1 ablation. These data indicate that long-term ablation of NHE1 activity increases the redox potential, mitigates high-fat diet-induced myocardial stress and fatty liver disease, leads to better preservation of insulin sensitivity, and may alter both cardiac and systemic metabolic substrate handling in mice.

PubMed ID: 24080184 Exiting the NIEHS site

MeSH Terms: Animals; Biological Transport; Blood Glucose/metabolism; Calcium/metabolism; Cardiotonic Agents/metabolism; Cation Transport Proteins/deficiency*; Cation Transport Proteins/metabolism; Diet, High-Fat; Energy Metabolism/genetics; Female; Gene Expression Regulation; Insulin Resistance; Insulin/blood; Male; Mice; Mice, Knockout; Myocardium/metabolism*; Myocardium/pathology*; Oxidation-Reduction; Oxidative Stress*/genetics; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers/metabolism; Sodium/metabolism; Troponin I/metabolism

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