title: Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress.
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. Immunoblotting results demonstrated that cardiac PDH E1α deficiency leads to an impaired ischemic AMP-activated protein kinase activation through Sestrin2-liver kinase B1 interaction which is responsible for an increased susceptibility of PDH E1α-deficient heart to ischemic insults. Thus, cardiac PDH E1α deficiency impairs ischemic AMP-activated protein kinase signaling and sensitizes hearts to the toxicological actions of ischemic stress.
authors.affiliation: *The First Affiliated Hospital of Jilin University, Changchun 130000, China Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Sun
authors.affiliation: *The First Affiliated Hospital of Jilin University, Changchun 130000, China Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Nanhu
authors.initials: N
authors.lastname: Quan
authors.affiliation: *The First Affiliated Hospital of Jilin University, Changchun 130000, China Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Chu
authors.affiliation: *The First Affiliated Hospital of Jilin University, Changchun 130000, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: *The First Affiliated Hospital of Jilin University, Changchun 130000, China.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: *The First Affiliated Hospital of Jilin University, Changchun 130000, China jli3@umc.edu.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Leng
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216 jli3@umc.edu.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005355:Fibrosis; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D000067268:Isolated Heart Preparation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010544:Peroxidases; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D005947:Glucose; D009687:Nuclear Proteins; D010544:Peroxidases; D017346:Protein Serine-Threonine Kinases; D030481:Pyruvate Dehydrogenase (Lipoamide); C529380:Sesn2 protein, mouse; D000084622:Sestrins; C065640:pyruvate dehydrogenase E1alpha subunit; C491654:Stk11 protein, mouse
keywords: AMP-activated protein kinase.; myocardial infarction; pyruvate dehydrogenase