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.
Keywords: Extracellular matrix, Collagen type I, III, fibronectin, gene expression, smooth muscle cells, RhoA, lovastatin, mevalonate,
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