Carvedilol Inhibits Angiotensin II-Induced Proliferation and Contraction in Hepatic Stellate Cells through the RhoARho-Kinase Pathway

Abstract EN

Aim.

Carvedilol is a nonselective beta-blocker used to reduce portal hypertension.

This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction.

Methods.

The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8).

Cell cycle progression and apoptosis in HSCs were determined by flow cytometry.

A collagen gel assay was used to confirm HSC contraction.

The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining.

Western blot analyses were performed to detect the expression of collagen I, collagen III, α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others.

Results.

The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner.

Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs.

Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference.

In addition, carvedilol reduced α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice.

The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2.

Conclusions.

The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis.

Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway.