Sirtuin1 protects endothelial Caveolin-1 expression and preserves endothelial function via suppressing miR-204 and endoplasmic reticulum stress.
Sirtuin1 (Sirt1) is a class III histone deacetylase that regulates a variety of physiological processes, including endothelial function. Caveolin1 (Cav1) is also an important determinant of endothelial function. We asked if Sirt1 governs endothelial Cav1 and endothelial function by regulating miR-204 expression and endoplasmic reticulum (ER) stress. Knockdown of Sirt1 in endothelial cells, and in vivo deletion of endothelial Sirt1, induced endothelial ER stress and miR-204 expression, reduced Cav1, and impaired endothelium-dependent vasorelaxation. All of these effects were reversed by a miR-204 inhibitor (miR-204 I) or with overexpression of Cav1. A miR-204 mimic (miR-204 M) decreased Cav1 in endothelial cells. In addition, high-fat diet (HFD) feeding induced vascular miR-204 and reduced endothelial Cav1. MiR-204-I protected against HFD-induced downregulation of endothelial Cav1. Moreover, pharmacologic induction of ER stress with tunicamycin downregulated endothelial Cav1 and impaired endothelium-dependent vasorelaxation that was rescued by overexpressing Cav1. In conclusion, Sirt1 preserves Cav1-dependent endothelial function by mitigating miR-204-mediated vascular ER stress.
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Modar
M
Kassan
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Ajit
A
Vikram
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Young-Rae
YR
Kim
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Qiuxia
Q
Li
University of California, San Diego, USA.
Adam
A
Kassan
VA San Diego Healthcare System, University of California, San Diego, USA.
Hemal H
HH
Patel
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Santosh
S
Kumar
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Mohanad
M
Gabani
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Jing
J
Liu
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Julia S
JS
Jacobs
Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
Kaikobad
K
Irani
D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D042783:Endothelial Cells / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D056564:Sirtuin 1 / Q000378:metabolism*; D014664:Vasodilation
D051242:Caveolin 1; C574692:MIRN204 microRNA, mouse; D035683:MicroRNAs; D056564:Sirtuin 1