Natarajan R, Pei H, Gu J L, Sarma J M, Nadler J
Department of Diabetes, Endocrinology and Metabolism, Gonda Diabetes Center, City of Hope Medical Center, Duarte, CA 91010, USA.
Cardiovasc Res. 1999 Feb;41(2):489-99. doi: 10.1016/s0008-6363(98)00312-5.
Vascular smooth muscle cell (VSMC) migration and proliferation are key events in the development of atherosclerosis and restenosis following angioplasty. These events are mediated by several growth factors and cytokines whose cellular effects include activation of phospholipases and arachidonic acid metabolism via the lipoxygenase (LO) pathway. Since 12-LO products have potent growth and chemotactic effects, we have examined if 12-LO is upregulated in the neointima of injured rat carotid arteries and also if LO inhibition could attenuate neointimal thickening.
The left common carotid arteries of male Sprague Dawley rats were injured using a 1.8 F PTCA balloon catheter. Four-fourteen days after injury, injured and uninjured tissue samples were processed for histology, and immunohistochemistry or polymerase chain reaction (PCR) to examine 12-LO expression.
Twelve days after injury, immunohistochemical staining with a 12-LO antibody revealed intense staining in injured left carotid arteries, mainly in neointimal VSMCs and inflammatory cells, but not in the uninjured right arteries. There was also a marked upregulation of 12-LO mRNA (over five-fold by competitive PCR) in the injured arteries. Treatment of the arteries with a LO inhibitor, phenidone, soon after injury resulted in significant inhibition of neointimal thickening. In contrast, a cyclooxygenase inhibitor, ibuprofen, had no effect.
These results indicate for the first time that balloon injury results in marked induction of 12-LO mRNA and protein expression in the vessel wall. Furthermore, LO pathway activation may mediate, at least in part, the development of the lesion or plaque instability, suggesting a novel target for therapeutic intervention to block these pathological events.
血管平滑肌细胞（VSMC）迁移和增殖是动脉粥样硬化发展以及血管成形术后再狭窄的关键事件。这些事件由多种生长因子和细胞因子介导，其细胞效应包括磷脂酶激活以及通过脂氧合酶（LO）途径的花生四烯酸代谢。由于12-LO产物具有强大的生长和趋化作用，我们研究了12-LO在损伤的大鼠颈动脉内膜中是否上调，以及LO抑制是否能减轻内膜增厚。
使用1.8F PTCA球囊导管损伤雄性Sprague Dawley大鼠的左颈总动脉。损伤后4-14天，对损伤和未损伤的组织样本进行组织学、免疫组织化学或聚合酶链反应（PCR）处理，以检测12-LO表达。
损伤后12天，用12-LO抗体进行免疫组织化学染色显示，损伤的左颈动脉有强烈染色，主要在内膜VSMC和炎症细胞中，而未损伤的右动脉中没有。损伤动脉中12-LO mRNA也有明显上调（通过竞争性PCR超过五倍）。损伤后不久用LO抑制剂非那吡啶处理动脉，可显著抑制内膜增厚。相比之下，环氧化酶抑制剂布洛芬没有效果。
这些结果首次表明球囊损伤导致血管壁中12-LO mRNA和蛋白表达明显诱导。此外，LO途径激活可能至少部分介导病变或斑块不稳定的发展，提示了一个用于阻断这些病理事件的治疗干预新靶点。
