Antiinflammatory and antiarteriosclerotic effects of pioglitazone
Antiinflammatory and antiarteriosclerotic effects of pioglitazone
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DOI：
10.1161/01.hyp.0000036396.64769.c2
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发表时间：
2002-11-01
期刊：
影响因子：
8.3
通讯作者：
Takeshita, A
中科院分区：
文献类型：
--
作者：
Ishibashi, M;Egashira, K;Takeshita, A
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）配体广泛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PPARgamma激活对动脉硬化的影响是重要的。通过给予大鼠N-ω-硝基-L-精氨酸甲酯（L-NAME）长期抑制内皮NO合成可诱导冠状血管炎症（单核细胞浸润，单核细胞趋化蛋白-1（MCP-1）表达）和随后的动脉硬化。我们检查了吡格列酮（一种PPARgamma配体）在该大鼠模型中的作用，以确定吡格列酮激活PPARgamma是否通过其对代谢状况的间接作用或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NO水平，但可以防止L-NAME诱导的冠状动脉炎症和动脉硬化。吡格列酮没有降低局部MCP-1的表达，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（CCR 2）的表达增加。吡格列酮激活PPARgamma可预防冠状动脉粥样硬化，可能是通过其抑制作用（下调循环单核细胞中的CCR 2）。抑制CCR 2介导的炎症可能代表新的免疫抑制。吡格列酮的作用不限于改善代谢状态。
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) 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.