Sirtuin1 contributes to the overexpression of Giα proteins and hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats.

ABSTRACT

BACKGROUND: We earlier demonstrated that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit the overexpression of Giα proteins and hyperproliferation that is attributed to the enhanced levels of endogenous angiotensin II (Ang II). In addition, the implication of Sirtuin1 (Sirt1) a histone deacetylase class III family in Ang II-induced hypertension has also been shown. We recently demonstrated that Ang II increased the expression of Sirt1 in aortic VSMC that contributed to the overexpression of Giα proteins. However, whether Sirt1 is overexpressed in VSMC from SHR and is linked to the enhanced expression of Giα proteins and hyperproliferation remains unexplored. METHOD AND RESULTS: In the present study, we show that Sirt1 is upregulated in VSMC from SHR and this upregulation was attenuated by AT1 receptor antagonist losartan. In addition, the inhibition or knockdown of Sirt1 by specific inhibitors EX 527 and NAM and/or siRNA attenuated the enhanced expression of Giα proteins, cell cycle proteins and hyperproliferation of VSMC from SHR. Furthermore, the enhanced levels of reactive oxygen species (ROS), hydrogen peroxide and NADPH oxidase subunits NOX2 and p47phox, increased phosphorylation of EGFR, ERK1/2 and AKT displayed by VSMC from SHR were also attenuated by knocking down of Sirt1 by siRNA. CONCLUSION: In summary, our results demonstrate that Sirt1 is overexpressed in VSMC from SHR which through augmenting oxidative stress contributes to the enhanced expression of Giα proteins, cell cycle proteins and resultant hyperproliferation of VSMC.