Panda D, Kundu G C, Lee B I, Peri A, Fohl D, Chackalaparampil I, Mukherjee B B, Li X D, Mukherjee D C, Seides S, Rosenberg J, Stark K, Mukherjee A B
Section on Developmental Genetics, Heritable Disorders Branch, Building 10, Room 9S241, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9308-13. doi: 10.1073/pnas.94.17.9308.
Angioplasty procedures are increasingly used to reestablish blood flow in blocked atherosclerotic coronary arteries. A serious complication of these procedures is reocclusion (restenosis), which occurs in 30-50% of patients. Migration of coronary artery smooth muscle cells (CASMCs) to the site of injury caused by angioplasty and subsequent proliferation are suggested mechanisms of reocclusion. Using both cultured human CASMCs and coronary atherectomy tissues, we studied the roles of osteopontin (OPN) and one of its receptors, alphavbeta3 integrin, in the pathogenesis of coronary restenosis. We also measured the plasma levels of OPN before and after angioplasty and determined the effect of exogenous OPN on CASMC migration, extracellular matrix invasion, and proliferation. We found that cultured CASMCs during log phase of growth and smooth muscle cell layer of the coronary atherosclerotic tissues of patients express both OPN mRNA and protein at a significantly elevated level compared with controls. Interestingly, whereas the baseline plasma OPN levels in control samples were virtually undetectable, those in patient plasma were remarkably high. We also found that interaction of OPN with alphavbeta3 integrin, expressed on CASMCs, causes migration, extracellular matrix invasion, and proliferation. These effects were abolished when OPN or alphavbeta3 integrin gene expression in CASMCs was inhibited by specific antisense S-oligonucleotide treatment or OPN-alphavbeta3 interaction was blocked by treatment of CASMCs with antibodies against OPN or alphavbeta3 integrin. Our results demonstrate that OPN and alphavbeta3 integrin play critical roles in regulating cellular functions deemed essential for restenosis. In addition, these results raise the possibility that transient inhibition of OPN gene expression or blocking of OPN-alphavbeta3 interaction may provide a therapeutic approach to preventing restenosis.
血管成形术越来越多地用于重建阻塞的动脉粥样硬化冠状动脉中的血流。这些手术的一个严重并发症是再闭塞（再狭窄），30%至50%的患者会出现这种情况。冠状动脉平滑肌细胞（CASMCs）迁移至血管成形术造成的损伤部位并随后增殖，被认为是再闭塞的机制。我们使用培养的人CASMCs和冠状动脉旋切组织，研究了骨桥蛋白（OPN）及其受体之一αvβ3整合素在冠状动脉再狭窄发病机制中的作用。我们还测量了血管成形术前和术后血浆中OPN的水平，并确定了外源性OPN对CASMC迁移、细胞外基质侵袭和增殖的影响。我们发现，与对照组相比，处于生长对数期的培养CASMCs以及患者冠状动脉粥样硬化组织的平滑肌细胞层中，OPN mRNA和蛋白的表达水平均显著升高。有趣的是，对照组样本中的基线血浆OPN水平几乎检测不到，而患者血浆中的水平却非常高。我们还发现，OPN与CASMCs上表达的αvβ3整合素相互作用会导致迁移、细胞外基质侵袭和增殖。当通过特异性反义S-寡核苷酸处理抑制CASMCs中的OPN或αvβ3整合素基因表达，或用抗OPN或αvβ3整合素抗体处理CASMCs阻断OPN-αvβ3相互作用时，这些作用就会被消除。我们的结果表明，OPN和αvβ3整合素在调节对再狭窄至关重要的细胞功能中起关键作用。此外，这些结果增加了短暂抑制OPN基因表达或阻断OPN-αvβ3相互作用可能提供预防再狭窄治疗方法的可能性。
