Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease
Kyle Northcote Cowan, … , Peter Lloyd Jones, Marlene Rabinovitch
Kyle Northcote Cowan, … , Peter Lloyd Jones, Marlene Rabinovitch
Published January 1, 2000
Citation Information: J Clin Invest. 2000;105(1):21-34. https://doi.org/10.1172/JCI6539.
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Article

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

Abstract

Increased expression of the glycoprotein tenascin-C (TN) is associated with progression of clinical and experimental pulmonary hypertension. In cultured smooth muscle cells (SMCs) TN is induced by matrix metalloproteinases (MMPs) and amplifies the proliferative response to growth factors. Conversely, suppression of TN leads to SMC apoptosis. We now report that hypertrophied 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 associated with reduced TN, suppression of SMC proliferation, and induction of apoptosis. Selective repression of TN by transfecting pulmonary arteries with antisense/ribozyme constructs also induces SMC apoptosis and arrests progressive vascular thickening but fails to induce regression. This failure is related to concomitant expansion of a SMC population, which produces an alternative cell survival αvβ3 ligand, osteopontin (OPN), in response to pro-proliferative cues provided by a proteolytic environment. OPN rescues MMP inhibitor–induced SMC apoptosis, and αvβ3 blockade induces apoptosis in hypertrophied arteries. Our data suggest that proteinase inhibition is a novel strategy to induce regression of vascular disease because this overcomes the pluripotentiality of SMC-matrix survival interactions and induces coordinated apoptosis and resorption of matrix.

Authors

Kyle Northcote Cowan, Peter Lloyd Jones, Marlene Rabinovitch

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Figure 1

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TN antisense cRNA. The hypothesized conformation of the TN antisense cRN...
TN antisense cRNA. The hypothesized conformation of the TN antisense cRNA using the U1Bam pZeo mut EcoRI/SpeI expression vector backbone (schematic modified from ref. 27). The EcoRI and SpeI restriction sites are underlined. Hairpin loops at the 5′ and 3′ ends are shown, and the 32-bp antisense RNA described in the text is constructed to incorporate a hammerhead ribozyme such that it folds and hybridizes to the target TN mRNA at the location of the GUC consensus cleavage site (arrow, site of cleavage).