Ishibashi Minako, Egashira Kensuke, Hiasa Ken-ichi, Inoue Shujiro, Ni Weihua, Zhao Qingwei, Usui Makoto, Kitamoto Shiro, Ichiki Toshihiro, Takeshita Akira
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Hypertension. 2002 Nov;40(5):687-93. doi: 10.1161/01.hyp.0000036396.64769.c2.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma ligand) in this rat model to determine whether PPARgamma activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.
过氧化物酶体增殖物激活受体γ（PPARγ）配体广泛应用于胰岛素抵抗和糖尿病患者。由于冠状动脉疾病是这类患者的主要并发症，因此确定PPARγ激活对动脉硬化的影响非常重要。通过给大鼠施用N（ω）-硝基-L-精氨酸甲酯（L-NAME）长期抑制内皮一氧化氮合成会诱导冠状动脉血管炎症（单核细胞浸润、单核细胞趋化蛋白-1 [MCP-1]表达）以及随后的动脉硬化。我们在这个大鼠模型中研究了吡格列酮（一种PPARγ配体）的作用，以确定吡格列酮激活PPARγ是通过其对代谢状况的间接作用还是通过对参与动脉硬化发病机制的细胞的直接作用来抑制动脉硬化。我们发现吡格列酮不影响代谢状态、收缩压或血清一氧化氮水平，但确实能预防L-NAME诱导的冠状动脉炎症和动脉硬化。吡格列酮没有降低MCP-1的局部表达，但显著减弱了病变和循环单核细胞中MCP-1受体C-C趋化因子受体2（CCR2）表达的增加。吡格列酮激活PPARγ可能通过其抗炎作用（下调循环单核细胞中的CCR2）预防冠状动脉硬化。抑制CCR2介导的炎症可能代表了吡格列酮除改善代谢状态之外的新型抗炎作用。
