title: Increased myocardial susceptibility to repetitive ischemia with high-fat diet-induced obesity.
abstract: Obesity and diabetes are frequently associated with cardiovascular disease. When a normal heart is subjected to brief/sublethal repetitive ischemia and reperfusion (I/R), adaptive responses are activated to preserve cardiac structure and function. These responses include but are not limited to alterations in cardiac metabolism, reduced calcium responsiveness, and induction of antioxidant enzymes. In a model of ischemic cardiomyopathy inducible by brief repetitive I/R, we hypothesized that dysregulation of these adaptive responses in diet-induced obese (DIO) mice would contribute to enhanced myocardial injury. DIO C57BL/6J mice were subjected to 15 min of daily repetitive I/R while under short-acting anesthesia, a protocol that results in the development of fibrotic cardiomyopathy. Cardiac lipids and candidate gene expression were analyzed at 3 days, and histology at 5 days of repetitive I/R. Total free fatty acids (FFAs) in the cardiac extracts of DIO mice were significantly elevated, reflecting primarily the dietary fatty acid (FA) composition. Compared with lean controls, cardiac FA oxidation (FAO) capacity of DIO mice was significantly higher, concurrent with increased expression of FA metabolism gene transcripts. Following 15 min of daily repetitive I/R for 3 or 5 days, DIO mice exhibited increased susceptibility to I/R and, in contrast to lean mice, developed microinfarction, which was associated with an exaggerated inflammatory response. Repetitive I/R in DIO mice was associated with more profound significant downregulation of FA metabolism gene transcripts and elevated FFAs and triglycerides. Maladaptive metabolic changes of FA metabolism contribute to enhanced myocardial injury in diet-induced obesity.
authors.affiliation: Section of Atherosclerosis and Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Geeta D
authors.initials: GD
authors.lastname: Thakker
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
authors.forename: Pawel T
authors.initials: PT
authors.lastname: Zymek
authors.forename: Saumya
authors.initials: S
authors.lastname: Sharma
authors.forename: Joe L
authors.initials: JL
authors.lastname: Raya
authors.forename: Philip M
authors.initials: PM
authors.lastname: Barger
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D053818:Chymases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D017202:Myocardial Ischemia / Q000209:etiology* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D015820:Cadherins; D005227:Fatty Acids; D007328:Insulin; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D014280:Triglycerides; C070896:M-cadherin; D053818:Chymases; C509230:Mcpt1 protein, mouse