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.
View: Text | PDF
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

×

Figure 12

Options: View larger image (or click on image) Download as PowerPoint
Suppression of OPN by proteinase inhibition and detection of OPN by immu...
Suppression of OPN by proteinase inhibition and detection of OPN by immunohistochemistry in PAs cultured in the presence or absence of selective proteinase inhibitors. Representative photomicrographs indicate that whereas OPN is deposited in the absence of proteinase inhibition with vehicles (a) DMSO for GM-6001 and (c) PEG for 1K, the presence of GM-6001 (b) or 1K (d) resulted in the loss of OPN immunoreactivity. As quantified in (e), this retrospective examination showed that, like TN, OPN was suppressed by proteinase inhibition. Bars: 5 μm; graph bars: mean + SEM of 4 vessels; *P < 0.05 compared with vehicle control.