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

Clinical studies have shown that treatment with 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase inhibitors can stabilize atherosclerotic pla ques and slow their progression. One determinant of plaque stability and si ze is the composition of the vascular extracellular matrix. The aim of this study was to evaluate the effects of different HMG-CoA reductase inhibitor s on the expression of major components of the vascular extracellular matri x 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 mu mol/L), simvastatin ( 0.05-20 mu mol/L), and pravastatin (1-100 mu mol/L). RNA expression of the extracellular matrix proteins thrombospondin-1, fibronectin, collagen type I, and biglycan as well as expression of the cytokine TGF-beta 1 was determ ined by Northern blotting. Extracellular matrix protein secretion was visua lized by immunofluorescence. In addition, cell proliferation and viability were measured using BrDUELISAs, MTT-tests, and direct cell counting. Expression of thrombospondin-1 was significantly decreased after 24 h incub ations with lovastatin in concentrations as low as 1 mu mol/L. Coincubation with the cholesterol precursor mevalonate completely reversed this effect. The downregulation of thrombospondin-1 expression occured in the same conc entration range that also inhibited cell proliferation. In contrast, lovast atin 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 compou nd pravastatin, had a similar effect on extracellular matrix expression as lovastatin. In summary, lovastatin and simvastatin predominantly decrease the expressio n of the glycoprotein thrombospondin-1, which is functionally associated wi th smooth muscle cell migration and proliferation. In contrast, expression of plaque-stabilizing extracellular proteins such as collagen type I and bi glycan are much less affected.