NYMC Faculty Publications

Sirtuin 1 Ablation in Endothelial Cells is Associated With Impaired Angiogenesis and Diastolic Dysfunction

Author Type(s)

Faculty

DOI

10.1152/ajpheart.00281.2014

Journal Title

American Journal of Physiology

First Page

1691

Last Page

1704

Document Type

Article

Publication Date

12-15-2014

Department

Medicine

Keywords

Age Factors, Animals, Cardiomegaly, Coronary Vessels, Diastole, Endothelium, Vascular, Fibrosis, Heart Ventricles, Human Umbilical Vein Endothelial Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Neovascularization, Physiologic, RNA, Messenger, Receptors, Vascular Endothelial Growth Factor, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Sirtuin 1, Vascular Endothelial Growth Factor A, Ventricular Function

Disciplines

Medicine and Health Sciences

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.

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