Effect of HMG-CoA Reductase Inhibition on Vascular Smooth Muscle Cells Extracellular Matrix Production: Role of RhoA

Abstract

Cholesterol-lowering effects apart, statins can improve the endothelial function, stabilize the atherosclerotic plaques, decrease the oxidative stress and inflammation and inhibit the thrombogenic response by means of the inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. We aimed to evaluate whether the effect of statins on RhoA activity mediate extracellular matrix production, particularly affecting collagen type I, in smooth muscle cells (SMCs). Our results showed that lovastatin decreased collagen expression in primary cultured chicken SMCs as determined by incorporation of [H3]-proline, RT-PCR and immunocytochemistry. This fall was parallel to that found in Rho A activity. Similar results were found when GGTI-298, a RhoA inhibitor, was added to the culture medium. Mevalonate or geranylgeranyl pyrophosphate reverted these effects. In order to elucidate the role of Rho A in these events we transfected the cell line A10 (rat SMCs) with constitutively active (G14V) or dominant negative RhoA (T19N) constructs. The last ones showed similar results regarding collagen production that those stated above in lovastatin treated primary SMC cultures. Constitutively active RhoA transfected cells showed the opposite effects. Next we performed a promoter activity assay to exclude post-transcriptional mechanisms implicated in these studies. We found a similar pattern in col1a2 promoter activity to that found in collagen expression. Our results have demonstrated that statins regulate the activation of RhoA through its isoprenylation, which is crucial for the regulation of extracellular matrix synthesis in SMCs.

Inhibitory effect of lovastatin on human lung cancer cell proliferation by regulating the ERK1/2 and COX-2 pathways

“…Lovastatin is an inhibitor of HMG-CoA reductase in the process of cholesterol synthesis. It can effectively suppress cholesterol synthesis and is therefore applied to hypercholesterolemia treatment in the clinic ( 13 , 14 ). Besides its lipid-lowering function, there is evidence to suggest that lovastatin can inhibit tumor cell proliferation, angiogenesis, invasion, and metastasis, and can induce apoptosis ( 15 , 16 ).…”

The Interaction of Immune System in Tumour Microenvironment and Possible Role of Cancer Cell Immnunosensitization for Better Treatment Efficacy: A Review

“…Additionally, along with their cholesterol-lowering effects, numerous investigations have demonstrated that statins have immunomodulatory activities via mevalonate-independent and -dependent mechanisms (Sarrabayrouse et al, 2017). They suppress the activity of GTPases belonging to the Ras and Rho families, which govern a variety of cellular activities, including cell death, metastasis, and immunological responses (Palomino-Morales et al, 2016). Statins also affect the immune system by inhibiting the generation of pro-inflammatory cytokines and activating CD8+ T cells (Côté-Daigneault et al, 2016).…”