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 5

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Quantitative analysis of apoptosis and proliferation. Counts of apoptoti...
Quantitative analysis of apoptosis and proliferation. Counts of apoptotic cells assessed by TUNEL positivity are displayed. (a) Proteinase inhibitors α1-PI, GM-6001, and 1K induce apoptosis in Mct vessels assessed after 8 days in organ culture. (b) Induction of apoptosis with proteinase inhibitors is not observed in control PAs from saline-injected rats. (c) Immunohistochemistry for PCNA was used as an indicator of proliferating vascular cells and quantified as a percent of total cells. Proliferation, which is induced by Mct, is greatly increased after 8 days in organ culture in the presence of inhibitor vehicles (except DMSO) and suppressed by all 3 inhibitors. Bars: mean + SEM of 3 vessels; *P < 0.05 compared with vehicle control; P < 0.05 compared to preculture Mct.