Nakamura Taishi, Yamamoto Eiichiro, Kataoka Keiichiro, Yamashita Takuro, Tokutomi Yoshiko, Dong Yi-Fei, Matsuba Shinji, Ogawa Hisao, Kim-Mitsuyama Shokei
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Hypertension. 2008 Feb;51(2):296-301. doi: 10.1161/HYPERTENSIONAHA.107.099044. Epub 2007 Dec 24.
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 cardiovascular 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 p22(phox) 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.
过氧化物酶体增殖物激活受体γ激动剂吡格列酮对高血压性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性心血管损伤的影响以及吡格列酮与1型血管紧张素受体阻滞剂联合使用的意义。将易中风自发性高血压大鼠（SHRSP）口服给予吡格列酮、坎地沙坦或吡格列酮与坎地沙坦联合用药4周，以比较它们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）来预防高血压性心血管损伤。吡格列酮与坎地沙坦联合使用比单一疗法更能抑制SHRSP的心脏肥大、炎症和间质纤维化，并比单一疗法更能减少SHRSP的血管内皮功能障碍。此外，它们联合使用对心血管损伤的更有益作用与NADPH氧化酶介导的心血管ROS的更多减少有关。为了阐明潜在的分子机制，我们检测了心血管NADPH氧化酶亚基。吡格列酮单一疗法显著降低了SHRSP心血管中的p22(phox)和Rac1，而吡格列酮与坎地沙坦联合使用更能降低p22(phox)并显著降低Nox1。因此，联合使用对心血管NADPH氧化酶的相加抑制作用归因于其对p22(phox)和Nox1蛋白水平的相加降低。总之，我们表明吡格列酮可预防高血压性心血管损伤，吡格列酮与坎地沙坦联合使用通过更多地抑制ROS对高血压性心血管损伤发挥更有益的作用。
