Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress

Toxicological Sciences : an Official Journal of the Society of Toxicology
Wanqing SunJ Li

Abstract

Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. We generated inducible cardiac-specific PDH E1α knockout (CreER(T2)-PDH(flox/flox)) mice that demonstrated a high mortality rate. It was hypothesized that PDH modulating cardiac glucose metabolism is crucial for heart functions under normal physiological and/or stress conditions. The myocardial infarction was conducted by a ligation of the left anterior descending coronary arteries. Cardiac PDH E1α deficiency caused large myocardial infarcts size and macrophage infiltration in the hearts (P < .01 vs wild-type [WT]). Wheat germ agglutinin and Masson trichrome staining revealed significantly increased hypertrophy and fibrosis in PDH E1α-deficient hearts (P < .05 vs WT). Measurements of heart substrate metabolism in an ex vivo working heart perfusion system demonstrated a significant impairment of glucose oxidation in PDH E1α-deficient hearts during ischemia/reperfusion (P < .05 vs WT). Dichloroacetate, a PDH activator, increased glucose oxidation in WT hearts during ischemia/reperfusion and reduced myocardial infarct size in WT, but not in PDH E1α-deficient hearts. Immuno...Continue Reading

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Citations

Apr 30, 2017·American Journal of Physiology. Heart and Circulatory Physiology·Dolena LedeeMichael A Portman
Aug 29, 2018·American Journal of Physiology. Endocrinology and Metabolism·Kristoffer SvenssonSimon Schenk
Oct 30, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Xuan LiJi Li
Jun 9, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nanhu QuanJi Li
Mar 22, 2018·Frontiers in Cardiovascular Medicine·Keshav GopalJohn Reyes Ussher
Mar 7, 2019·Frontiers in Cardiovascular Medicine·Qun ChenEdward J Lesnefsky
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Dec 15, 2020·Free Radical Biology & Medicine·Yunxia LiuNanhu Quan
Oct 28, 2020·Nature Metabolism·Kyle S McCommisBrian N Finck
May 14, 2021·Circulation Research·Gary D LopaschukE Dale Abel

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