CA2-MATRIX( CHANNEL BLOCKERS MODULATE METABOLISM OF COLLAGENS WITHIN THE EXTRACELLULAR)

The extracellular matrix (ECM) is an intricate network composed of an array of macromolecules capable of regulating the functional responsiv eness of cells. Its composition greatly varies among different types o f tissue, and dysregulation of its metabolism may contribute to vascul ar remodeling during the pathogenesis of various diseases, including a therosclerosis. In view of their antiatherosclerotic effects, the role of Ca2+ channel blockers in the metabolism of ECM was examined. Nanom olar concentrations of the five Ca2+ channel blockers amlodipine, felo dipine, manidipine, verapamil, or diltiazem significantly decreased bo th the constitutive and platelet-derived growth factor BB dependent co llagen deposition in the ECM formed by human vascular smooth muscle ce lls and fibroblasts. The drugs inhibited the expression of fibrillar c ollagens type I and III and of basement membrane type IV collagen. Fur thermore, Ca2+ channel blockers specifically increased the proteolytic activity of the 72-kDa type IV collagenase as shown by gelatin zymogr aphy and inhibited the transcription of tissue inhibitor of metallopro teinases-2.