title: Cardiac steatosis potentiates angiotensin II effects in the heart.
abstract: Lipid accumulation in the heart is associated with obesity and diabetes and may play an important role in the pathogenesis of heart failure. The renin-angiotensin system is also thought to contribute to cardiovascular morbidity in obese and diabetic patients. We hypothesized that the presence of lipid within the myocyte might potentiate the cardiomyopathic effects of ANG II in the cardiac diacylglycerol acyl transferase 1 (DGAT1) transgenic mouse model of myocyte steatosis. Treatment with ANG II resulted in a similar increase in blood pressure in both nontransgenic and DGAT1 transgenic mice. However, ANG II in DGAT1 transgenic mice resulted in a marked increase in interstitial fibrosis and a reduction in systolic function compared with nontransgenic littermates. Lipidomic analysis revealed that >20% of lipid species were significantly altered between nontransgenic and DGAT1 transgenic animals, whereas 3% were responsive to ANG II administration. ROS were also increased by ANG II in DGAT1 transgenic hearts. ANG II treatment resulted in increased expression of transforming growth factor (TGF)-β2 and the type I TGF-β receptor as well as increased phosphorylation of Smad2 in DGAT1 transgenic hearts. Injection of neutralizing antibodies to TGF-β resulted in a reduction in fibrosis in DGAT1 transgenic hearts treated with ANG II. These results suggest that myocyte steatosis amplifies the fibrotic effects of ANG II through mechanisms that involve activation of TGF-β signaling and increased production of ROS.
authors.affiliation: Department of Medicine and the Diabetes Center, University of California, San Francisco, California; dglenn@diabetes.ucsf.edu.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Glenn
authors.affiliation: Department of Medicine and the Diabetes Center, University of California, San Francisco, California;
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Cardema
authors.affiliation: Department of Medicine and the Diabetes Center, University of California, San Francisco, California;
authors.forename: Wei
authors.initials: W
authors.lastname: Ni
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Francisco, California; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Francisco, California; and.
authors.forename: Yerem
authors.initials: Y
authors.lastname: Yeghiazarians
authors.affiliation: West Coast Metabolomics Center, Genome Center, University of California, Davis, California.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Grapov
authors.affiliation: West Coast Metabolomics Center, Genome Center, University of California, Davis, California.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Medicine and the Diabetes Center, University of California, San Francisco, California;
authors.forename: David G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050356:Lipid Metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D014280:Triglycerides; D000804:Angiotensin II; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
keywords: angiotensin; diacylglycerol acyl transferase 1; fibrosis; lipotoxixity; transforming growth factor-β