title: Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction.
abstract: Discordant myocardial growth and angiogenesis can explain left ventricular (LV) hypertrophy progressing toward heart failure with aging. Sirtuin 1 expression declines with age; therefore we explored the role played by angiogenesis and Sirtuin 1 in the development of cardiomyopathy. We compared the cardiac function of 10- to 15-wk-old (wo), 30-40 wo, and 61-70 wo endothelial Sirtuin 1-deleted (Sirt1(endo-/-)) mice and their corresponding knockout controls (Sirt1(Flox/Flox)). After 30-40 wk, Sirt1(endo-/-) animals exhibited diastolic dysfunction (DD), decreased mRNA expression of Serca2a in the LV, and decreased capillary density compared with control animals despite a similar VEGFa mRNA expression. However, LV fibrosis and hypoxia-inducible factor (HIF)1α expression were not different. The creation of a transverse aortic constriction (TAC) provoked more severe DD and LV fibrosis in Sirt1(endo-/-) compared with control TAC animals. Although the VEGFa mRNA expression was not different and the protein expression of HIF1α was higher in the Sirt1(endo-/-) TAC animals, capillary density remained reduced. In cultured endothelial cells administration of Sirtuin 1 inhibitor decreased mRNA expression of VEGF receptors FLT 1 and FLK 1. Ex vivo capillary sprouting from aortic explants showed impaired angiogenic response to VEGF in the Sirt1(endo-/-) mice. In conclusion, the data demonstrate 1) a defect in angiogenesis preceding development of DD; 2) dispensability of endothelial Sirtuin 1 under unstressed conditions and during normal aging; and 3) impaired angiogenic adaptation and aggravated DD in Sirt1(endo-/-) mice challenged with LV overload.
authors.affiliation: Medical Intensive Care Unit, Department of Nephrology and INSERM U-1088, University of Picardie, Amiens, France; Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York julien.maizel@u-picardie.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Chi Hua Sarah
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Medical Intensive Care Unit, Department of Nephrology and INSERM U-1088, University of Picardie, Amiens, France; Department of Nephrology and Rheumatology, University Medical Center, Gottingen, Germany; and.
authors.forename: Radovan
authors.initials: R
authors.lastname: Vasko
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D000367:Age Factors; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D003331:Coronary Vessels / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D003971:Diastole; D004730:Endothelium, Vascular / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D006352:Heart Ventricles / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D016276:Ventricular Function
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Adriamycin cardiomyopathy; VEGF; angiogenesis; echocardiography; hypoxia; transverse aortic constriction