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

Abstract

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.

Levistilide A reverses rat hepatic fibrosis by suppressing angiotensin II‑induced hepatic stellate cells activation

“…Therefore, numerous effective therapeutic approaches have focused on the raS, particularly Ang II (4,9). In accordance with previous studies (6,23,24), ang ii stimulation promoted the proliferation of HScs and upregulated the levels of α-SMA and F-actin in HSCs. Lev A treatment inhibited Ang II-induced HSC proliferation and activation, indicating that Lev A may be an effective agent in the treatment of hepatic fibrosis.…”

Individualizing Risk Prediction for Positive Coronavirus Disease 2019 Testing

“…6 Carvedilol was found recently to inhibit ACE2-induced proliferation and contraction in hepatic stellate cells through the rhoa/rho-kinase pathway. 28 It is unclear whether it has similar effects on ACE2 in lung endothelium. With ACE2 being key in the pathophysiologic findings of infection with SARS-CoV-2, our findings are intriguing.…”

Beta-blockers and Statins: Role in Portal Hypertension and Beyond

“…Thus, in the compensated phase of cirrhosis, slight reductions in portal pressure have already been shown to be beneficial during carvedilol use. Other effects of this drug, such as the hepatic antifibrotic effect, have previously been demonstrated and could explain the decrease in ascites development and a reduction in long-term mortality [10][11][12] . This benefit has not been found in studies with traditional beta-blockers.…”