HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways

Area of Science:

• Cardiovascular Biology
• Pharmacology
• Molecular Biology

Background:

• 3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) are beneficial for cardiovascular diseases.
• Angiotensin II (Ang II) promotes cardiovascular damage via profibrotic factors like connective tissue growth factor (CTGF).

Purpose of the Study:

• To investigate if statins modulate Ang II responses by evaluating CTGF expression and underlying mechanisms.
• To determine the role of RhoA signaling and other pathways in Ang II-induced CTGF production and statin's effect.

Main Methods:

• In vitro studies using cultured vascular smooth muscle cells (VSMCs) treated with statins and Ang II.
• In vivo studies using Ang II-infused rats treated with atorvastatin.
• Analysis of CTGF expression, RhoA activation, Rho kinase activity, MAPK pathways (p38MAPK, JNK), and redox processes.

Main Results:

• Statins (atorvastatin, simvastatin) inhibited Ang II-induced CTGF production in VSMCs.
• Statin's inhibitory effect was reversed by mevalonate and geranylgeranylpyrophosphate, indicating RhoA pathway involvement.
• Statins inhibited Ang II-induced RhoA membrane localization and activation, and downregulated p38MAPK, JNK, and redox processes.
• In rats, atorvastatin reduced aortic CTGF and Rho activation without altering blood pressure.

Conclusions:

• HMG-CoA reductase inhibitors (statins) inhibit Ang II-activated intracellular signaling pathways, including RhoA/Rho kinase, MAPK, and redox processes.
• These inhibited pathways are involved in the regulation of CTGF, a mediator of vascular fibrosis.
• The findings offer a potential explanation for the beneficial cardiovascular effects of statins.