Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease

Increased expression of the glycoprotein tenascin-C (TN) is associated with progression of clinical and experimental pulmonary hypertension. In cultur ed smooth muscle cells (SMCs) TN is induced by matrix metalloproteinases (M MPs) and amplifies the proliferative response to growth factors. Conversely , suppression of TN leads to SMC apoptosis. We flow report that hypertrophi ed rat pulmonary arteries in organ culture, which progressively thicken in association with cell proliferation and matrix accumulation, can be made to regress by inhibiting either serine elastases or MMPs. This effect is asso ciated with reduced TN, suppression of SMC proliferation, and induction of apoptosis. Selective repression of TN by transfecting pulmonary arteries wi th ancisense/ribozyme constructs also induces SMC apoptosis and arrests pro gressive vascular thickening but fails to induce regression. This failure i s related to concomitant expansion of a SMC population, which produces an a lternative cell survival alpha(v)beta(3) ligand, osteopontin (OPN), in resp onse to pro-proliferative cues provided by a proteolytic environment. OPN r escues MMP inhibitor-induced SMC apoptosis, and alpha(v)beta(3) blockade in duces apoptosis in hyper trophied arteries. Our data suggest that proteinas e inhibition is a novel strategy to induce regression of vascular disease b ecause this overcomes the pluripotentiality of SMC-matrix survival interact ions and induces coordinated apoptosis and resorption of matrix.