title: ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4.
abstract: The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.
authors: Department of Pediatrics, University of Alberta, Edmonton, Canada.
authors: Jun
authors: J
authors: Mori
authors: Osama Abo
authors: OA
authors: Alrob
authors: Cory S
authors: CS
authors: Wagg
authors: Robert A
authors: RA
authors: Harris
authors: Gary D
authors: GD
authors: Lopaschuk
authors: Gavin Y
authors: GY
authors: Oudit
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006321:Heart / Q000187:drug effects / Q000502:physiology; D054144:Heart Failure, Diastolic / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D056566:Sirtuin 3 / Q000378:metabolism
chemical_list: D005227:Fatty Acids; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; C525046:Sirt3 protein, mouse; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D056566:Sirtuin 3; D005947:Glucose