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

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• 作者：Vikram Prasad ; John N. Lorenz ; Marian L. Miller ; Kanimozhi Vairamani ; Michelle L. Nieman ; Yigang Wang ; Gary E. Shull
• 关键词：NHE-1 ; Slc9a1 ; Metabolic syndrome ; Diabetes ; Insulin resistance
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：December, 2013
• 年：2013
• 卷：65
• 期：Complete
• 页码：33-42
• 全文大小：1297 K

文摘

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^{鈭?鈭?/sup> 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鈭?鈭?/sup> 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鈭?鈭?/sup> 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鈭?鈭?/sup> 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鈭?鈭?/sup> hearts, as indicated by smaller increases in phosphorylation of Hsp25 and 伪-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鈭?鈭?/sup> 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.}