Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease
Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease
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DOI：
10.1172/jci6539
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发表时间：
2000-01-01
影响因子：
15.9
通讯作者：
Rabinovitch, M
中科院分区：
文献类型：
--
作者：
Cowan, KN;Jones, PL;Rabinovitch, M
糖蛋白生腱蛋白-C (TN) 表达的增加与临床和实验性肺动脉高压的进展相关。在培养的平滑肌细胞 (SMC) 中，TN 由基质金属蛋白酶 (MMP) 诱导，并放大对生长因子的增殖反应。相反，抑制 TN 会导致 SMC 凋亡。我们报道，器官培养中肥大的大鼠肺动脉随着细胞增殖和基质积累而逐渐增厚，可以通过抑制丝氨酸弹性蛋白酶或基质金属蛋白酶来使其消退。这种作用与减少 TN、抑制 SMC 增殖和诱导细胞凋亡有关。通过用反义/核酶构建体转染肺动脉来选择性抑制 TN 也会诱导 SMC 凋亡并阻止进行性血管增厚，但无法诱导消退。这种失败与 SMC 群体的伴随扩张有关，SMC 群体响应蛋白水解环境提供的促增殖信号而产生替代细胞存活 α(v)β(3) 配体骨桥蛋白 (OPN)。 OPN 可挽救 MMP 抑制剂诱导的 SMC 细胞凋亡，α(v)β(3) 阻断可诱导肥大动脉细胞凋亡。我们的数据表明，蛋白酶抑制是诱导血管疾病消退的一种新策略，因为这克服了 SMC-基质存活相互作用的多能性，并诱导协调的细胞凋亡和基质吸收。
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 flow 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 ancisense/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 alpha(v)beta(3) ligand, osteopontin (OPN), in response to pro-proliferative cues provided by a proteolytic environment. OPN rescues MMP inhibitor-induced SMC apoptosis, and alpha(v)beta(3) blockade induces apoptosis in hyper trophied 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.