Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan
Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan
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DOI：
10.1161/hypertensionaha.107.099044
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发表时间：
2008-02-01
期刊：
影响因子：
8.3
通讯作者：
Kim-Mitsuyama, Shokei
中科院分区：
文献类型：
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作者：
Nakamura, Taishi;Yamamoto, Eiichiro;Kim-Mitsuyama, Shokei
吡格列酮是一种过氧化物酶体增殖物激活受体γ激动剂，其对高血压心血管损伤的影响尚不清楚。我们研究了吡格列酮对高血压心血管损伤的影响以及吡格列酮与血管紧张素1型受体阻滞剂联合应用的意义。采用易卒中型自发性高血压大鼠（SHRSP）模型，分别口服吡格列酮、坎地沙坦或吡格列酮与坎地沙坦联合用药4周，比较其对心血管损伤的影响。吡格列酮在不降低血压的情况下，显著抑制心脏炎症和纤维化，并减少血管内皮功能障碍，这些有益作用与通过抑制心血管NADPH氧化酶减少超氧化物有关。因此，吡格列酮通过抑制活性氧（ROS）来保护高血压心血管损伤。吡格列酮和坎地沙坦联合用药抑制SHRSP心肌肥厚、炎症和间质纤维化的程度高于单药治疗，减少SHRSP血管内皮功能障碍的程度高于单药治疗。此外，它们的组合对心血管损伤的更多有益作用与更多NADPH氧化酶介导的心血管ROS的减少相关。为了阐明潜在的分子机制，我们研究了心血管NADPH氧化酶亚基。吡格列酮单药治疗可显着减弱SHRSP中的心血管p22（phox）和Rac 1，而吡格列酮与坎地沙坦联合治疗可更多地减弱p22（phox）并显着降低Nox 1。因此，联合用药对心血管NADPH氧化酶的叠加抑制归因于其对p22phox和Nox 1蛋白水平的叠加衰减。总之，我们发现吡格列酮可以保护高血压心血管损伤，吡格列酮和坎地沙坦联合使用可以通过更多地抑制ROS而对高血压心血管损伤产生更有益的作用。
The effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on hypertensive cardiovascular injury is unknown. We examined the effect of pioglitazone on hypertensive cardiovascular injury and the significance of combination of pioglitazone with angiotensin type 1 receptor blocker. Stroke-prone spontaneously hypertensive rats ( SHRSP) were orally given pioglitazone, candesartan, or combined pioglitazone and candesartan for 4 weeks to compare their effects on cardiovasucular injury. Pioglitazone, without lowering blood pressure, significantly suppressed cardiac inflammation and fibrosis and reduced vascular endothelial dysfunction, and these beneficial effects were associated with the reduction of superoxide by inhibition of cardiovascular NADPH oxidase. Thus, pioglitazone protects against hypertensive cardiovascular injury, by inhibiting reactive oxygen species ( ROS). Combination of pioglitazone and candesartan suppressed cardiac hypertrophy, inflammation, and interstitial fibrosis of SHRSP to a greater extent than either monotherapy, and reduced vascular endothelial dysfunction of SHRSP more than either monotherapy. Furthermore, more beneficial effects of their combination on cardiovascular injury were associated with more reduction of NADPH oxidase - mediated cardiovascular ROS. To elucidate the underlying molecular mechanism, we examined cardiovascular NADPH oxidase subunits. Pioglitazone monotherapy significantly attenuated cardiovascular p22(phox) and Rac1 in SHRSP, whereas pioglitazone combined with candesartan more attenuated p22(phox) and significantly reduced Nox1. Thus, additive suppression of cardiovascular NADPH oxidase by the combination was attributed to its additive attenuation of p22phox and Nox1 protein levels. In conclusion, we showed that pioglitazone protected against hypertensive cardiovascular damage, and the combination of pioglitazone and candesartan exerted more beneficial effects on hypertensive cardiovascular injury by more suppressing ROS.