Overexpression of SIRT1 in vascular smooth muscle cells attenuates angiotensin II-induced vascular remodeling and hypertension in mice.

Abstract

UNLABELLED:

Angiotensin II (AngII) induces the development of vascular hypertrophy and hypertension. We have shown previously that overexpression of class III deacetylase SIRT1 inhibits AngII-induced hypertrophy in vascular smooth muscle cells (VSMCs). However, the direct role of SIRT1 in VSMCs in response to AngII infusion in vivo remains unclear. Here, we found that the expression and activity of SIRT1 in mouse aortas was decreased significantly by AngII infusion. VSMC-specific SIRT1 transgene (SV-Tg) prevented the increase in systolic blood pressure (SBP) caused by AngII infusion without affecting heart function in mice. SIRT1 overexpression alleviated vascular remodeling in mouse thoracic and renal aortas induced by AngII infusion, and significantly inhibited reactive oxygen species (ROS) generation, vascular inflammation, and collagen synthesis in arterial walls. Reduced expression of transforming growth factor-β 1 (TGF-β1) was also observed in the aortas of AngII-infused SV-Tg mice. Moreover, SIRT1 overexpression decreased AngII-increased binding of nuclear factor-κB on its specific binding sites on TGF-β1 promoter. Taken together, these data demonstrate that SIRT1 overexpression in VSMCs reduces SBP and inhibits AngII-induced vascular remodeling in mice. The inhibition of vascular remodeling contributes, at least in part, to the antihypertensive effect of SIRT1.

KEY MESSAGE:

SIRT1 is reduced in aortas of AngII-infused hypertensive mice. SIRT1 VSMC transgene alleviates AngII-increased systolic blood pressure. SIRT1 VSMC transgene attenuates AngII-induced vascular remodeling. VSMC SIRT1 overexpression inhibits remodeling-related pathological changes. VSMC SIRT1 overexpression reduces AngII-induced TGF-β1 expression.

• Authors: Peng Gao, Ting-Ting Xu, Jie Lu, Li Li, Jing Xu, De-Long Hao, Hou-Zao Chen, De-Pei Liu
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 92 Issue 4 Pg. 347-57 (Apr 2014) ISSN: 1432-1440 [Electronic] Germany
• PMID: 24352856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Angiotensin II
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Angiotensin II
• Animals
• Aorta (enzymology, pathology, physiopathology)
• Epigenesis, Genetic
• Gene Expression
• Hypertension (chemically induced, enzymology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Muscle, Smooth, Vascular (enzymology)
• Myocytes, Smooth Muscle (enzymology)
• Reactive Oxygen Species (metabolism)
• Sirtuin 1 (genetics, metabolism)
• Vasculitis (chemically induced, enzymology)