Effect of HMG-CoA reductase inhibitors on extracellular matrix expression in human vascular smooth muscle cells

Abstract

Clinical studies have shown that treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can stabilize atherosclerotic plaques and slow their progression. One determinant of plaque stability and size is the composition of the vascular extracellular matrix. The aim of this study was to evaluate the effects of different HMG-CoA reductase inhibitors on the expression of major components of the vascular extracellular matrix in smooth muscle cells. Cultured human vascular smooth muscle cells were incubated for 24-72 h with the HMG-CoA reductase inhibitors lovastatin (1-50 micromol/L), simvastatin (0.05-20 micromol/L), and pravastatin (1-100 micromol/L). RNA expression of the extracellular matrix proteins thrombospondin-1, fibronectin, collagen type I, and biglycan as well as expression of the cytokine TGF-beta1 was determined by Northern blotting. Extracellular matrix protein secretion was visualized by immunofluorescence. In addition, cell proliferation and viability were measured using BrDU-ELISAs, MTT-tests, and direct cell counting. Expression of thrombospondin-1 was significantly decreased after 24 h incubations with lovastatin in concentrations as low as 1 micromol/L. Coincubation with the cholesterol precursor mevalonate completely reversed this effect. The downregulation of thrombospondin-1 expression occured in the same concentration range that also inhibited cell proliferation. In contrast, lovastatin did not affect expression of fibronectin, whereas collagen type I and biglycan expression decreased only after long incubations with high, toxic lovastatin concentrations. Simvastatin, but not the very hydrophilic compound pravastatin, had a similar effect on extracellular matrix expression as lovastatin. In summary, lovastatin and simvastatin predominantly decrease the expression of the glycoprotein thrombospondin-1, which is functionally associated with smooth muscle cell migration and proliferation. In contrast, expression of plaque-stabilizing extracellular proteins such as collagen type I and biglycan are much less affected.

Amelioration of Angiotensin II–Induced Cardiac Injury by a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor

“…In cultured VSMCs, HMG-CoA reductase inhibition diminished collagen I, thrombospondin, and fibronectin synthesis. 24 Similarly, HMG-CoA reductase inhibitors interfered with surface adhesion molecule expression by macrophages, leading to monocyte-endothelium adhesion inhibition. 25 Conceivably, the effects could also be related to a cholesterol-independent decreased AT1 receptor expression in response to statin treatment.…”

Cholesterol, Cytokines and Diseases

“…In an animal study using magnetic resonance imaging (MRI) post-myocardial infarction (MI) to assess remodelling, the effect of cerivastatin on attenuating hypertrophy after MI was completely abrogated by NOS inhibition (136)(137)(138). Statins are also known to inhibit mitogen-activated protein kinase (MAPK), and to interfere with cellular proliferation (139)(140)(141), the integrity of the actin cytoskeleton and the induction ofmatrix proteins (142)(143) , all important in the development of heart failure.…”

Statin-exposed vascular smooth muscle cells secrete proteoglycans with decreased binding affinity for LDL

“…Using cultured human smooth cells, one group has shown by Northern analysis that 72 h of lovastatin exposure decreases biglycan mRNA expression (46). This lovastatin effect was completely prevented with the coaddition of mevalonate.…”