Angiotensin II-induced overexpression of sirtuin 1 contributes to enhanced expression of Giα proteins and hyperproliferation of vascular smooth muscle cells

Area of Science:

• Molecular Biology
• Cardiovascular Physiology
• Epigenetics

Background:

• Angiotensin II (ANG II) is a key regulator of physiological functions, including vascular smooth muscle cell (VSMC) proliferation and hypertrophy, partly via Giα protein overexpression.
• Sirtuin 1 (Sirt1), a histone deacetylase, influences VSMC migration, growth, and is implicated in ANG II-induced hypertension.

Purpose of the Study:

• To investigate the role of Sirt1 in ANG II-induced Giα protein overexpression and aortic VSMC hyperproliferation.
• To elucidate the signaling pathways mediating Sirt1's effects in ANG II-stimulated VSMCs.

Main Methods:

• Treated VSMCs with ANG II and assessed Sirt1 expression.
• Utilized siRNA to knockdown Sirt1 and examined its effects on ANG II-induced VSMC proliferation, Giα protein levels, cell cycle proteins, oxidative stress markers, and receptor phosphorylation.
• Investigated the involvement of MAP kinase/Akt signaling pathways.

Main Results:

• ANG II treatment increased Sirt1 expression in VSMCs, which was blocked by AT1 and AT2 receptor antagonists.
• Sirt1 knockdown attenuated ANG II-induced overexpression of Giα-2, Giα-3, cell cycle proteins (cyclin D1, Cdk4, pRb), and reduced oxidative stress (superoxide anion, NADPH oxidase activity).
• Silencing Sirt1 also reduced ANG II-induced phosphorylation of ERK1/2, Akt, PDGFR, EGFR, and IGFR.

Conclusions:

• ANG II upregulates Sirt1 expression in VSMCs.
• Sirt1 mediates ANG II-induced VSMC hyperproliferation through oxidative stress and growth factor receptor-activated MAP kinase/Akt signaling.
• These findings highlight Sirt1 as a critical mediator in ANG II-induced VSMC dysfunction and hypertension.