Pioglitazone enhances cytokine-induced apoptosis in vascular smooth muscle cells and reduces intimal hyperplasia
Pioglitazone enhances cytokine-induced apoptosis in vascular smooth muscle cells and reduces intimal hyperplasia
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DOI：
10.1161/hc3001.092040
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发表时间：
2001-07-24
期刊：
影响因子：
37.8
通讯作者：
Kikuchi, K
中科院分区：
文献类型：
--
作者：
Aizawa, Y;Kawabe, J;Kikuchi, K
背景-细胞因子通过促进诱导型一氧化氮合酶(INOS)的激活，诱导血管疾病病变中的细胞凋亡。噻唑烷二酮类化合物是一种新型的胰岛素增敏剂，已被证明可以调节细胞因子诱导的NO的产生。我们研究了吡格列酮对体外培养的血管平滑肌细胞(VSMCs)和血管内膜发育过程中细胞凋亡的影响。方法与结果--吡格列酮(0.1~10mU/L)显著促进细胞因子诱导的大鼠血管平滑肌细胞诱导型一氧化氮合酶的表达和NO的产生，但天然的过氧化物酶体增殖物激活的受体-γ配体15-脱氧-三角洲(12，14)-前列腺素J2(高达10mU/L)对此无影响。吡格列酮还显著加剧了细胞活力的下降，TUNEL阳性细胞数量的增加证明了这一点。NO合成抑制剂N-单甲基-L-精氨酸可阻断吡格列酮的上述作用。在对球囊损伤的大鼠颈动脉进行的体内研究中，新生内膜厚度在损伤后2周达到最大水平。然后，用或不用吡格列酮(3mg.kg(-1).d(-1))喂养大鼠一周。与赋形剂对照组相比，吡格列酮治疗组大鼠颈动脉内膜/中膜面积比明显减少30%，新生内膜细胞凋亡率显著增加。结论吡格列酮以非依赖性的方式促进细胞因子激活的VSMCs的凋亡，并诱导大鼠颈动脉球囊损伤后内膜增生明显消退。吡格列酮似乎是血管病变中一种有效的细胞凋亡诱导剂，为预防血管介入治疗后再狭窄提供了一种新的药理学策略。
Background-Cytokines induce apoptosis in vascular disease lesions through enhancement of inducible nitric oxide (NO) synthase (iNOS) activation. The thiazolidinediones, novel insulin-sensitizing agents, have been demonstrated to modulate cytokine-induced NO production. We have investigated the role of pioglitazone in the apoptosis of vascular smooth muscle cells (VSMCs) in vitro and developed intimal. hyperplasia in vivo.Methods and Results-Pioglitazone (0.1 to 10 mu mol/L) significantly enhanced cytokine-induced expression of iNOS and NO production in a dose-dependent mariner in rat VSMCs, but 15-deoxy-Delta (12,14)-prostaglandin J2 (up to 10 mu mol/L), a native peroxisome proliferator-activated receptor-gamma ligand, showed no effect. Pioglitazone also significantly enhanced reduction of cell viability, as evidenced by the increase in the number of TUNEL-positive cells. All of these effects of pioglitazone were blocked by treatment with N-monomethyl-L-arginine, an NO synthesis inhibitor. In an in vivo study with a balloon-injured rat carotid artery, neointimal thickness had reached maximum levels at 2 weeks after injury. Then, rats were fed with or without pioglitazone (3 mg.kg(-1).d(-1)) for an additional week. The ratio of intima to media area of carotid artery was significantly decreased by 30%, and the ratio of apoptotic cells in neointima was significantly increased in pioglitazone-treated rats compared with vehicle-treated control rats.Conclusions-Pioglitazone enhanced apoptosis in an NO-dependent manner in cytokine-activated VSMCs and induced significant regression of intimal hyperplasia in balloon-injured rat carotid artery. It appears that pioglitazone is a potent apoptosis inducer in vascular lesions, providing a novel pharmacological strategy to prevent restenosis after vascular intervention.