Anti-atherogenic effects of the combination therapy with olmesartan and azelnidipine in diabetic apolipoprotein E-deficient mice.
Anti-atherogenic effects of the combination therapy with olmesartan and azelnidipine in diabetic apolipoprotein E-deficient mice.
复制标题
奥美沙坦和阿折地平联合治疗对糖尿病载脂蛋白 E 缺陷小鼠的抗动脉粥样硬化作用。
DOI：
10.1620/tjem.228.305
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
H. Shimokawa
中科院分区：
文献类型：
--
作者：
Kazuki Noda;Maki Hosoya;S. Nakajima;J. Ohashi;Y. Fukumoto;H. Shimokawa
许多研究旨在确定心血管医学中的抗动脉粥样硬化药物。我们最近证明，奥美沙坦（OLM，一种血管紧张素II受体阻滞剂）和阿折地平（AZL，一种二氢吡啶钙通道阻滞剂）的联合治疗可改善糖尿病载脂蛋白E缺陷（ApoE(-/-)）小鼠的内皮功能。在本研究中，我们检验了这种联合治疗是否也能抑制小鼠的动脉粥样硬化。我们使用了雄性对照小鼠和链脲佐菌素诱导的糖尿病ApoE(-/-)小鼠。糖尿病ApoE(-/-)小鼠分别用溶媒（未治疗组）、奥美沙坦（30mg/kg/天）、阿折地平（10mg/kg/天）、它们的联合用药（OLM + AZL）或肼屈嗪（HYD，5mg/kg/天，作为降压对照）进行口服治疗5周。在5周时，未治疗组的收缩压显著升高，而OLM + AZL组和HYD组的收缩压恢复正常。未治疗组的胸主动脉粥样硬化面积、冠状动脉血管周围纤维化和中层厚度增加，OLM + AZL组有所改善，而HYD组没有。用荧光探针二氢乙啶染色显示，未治疗组活性氧物质的产生增加，OLM + AZL组有所改善。与这些发现一致的是，未治疗组肾脏中的巨噬细胞浸润以及心脏、肾脏和肝脏中晚期糖基化终末产物受体的表达增加，OLM + AZL组均有所改善，同时伴有内皮型一氧化氮合酶（eNOS）的上调。总之，奥美沙坦和阿折地平的联合治疗通过抑制氧化应激和激活eNOS，在糖尿病ApoE(-/-)小鼠中发挥抗动脉粥样硬化作用，且与其降压作用无关。在临床上，这种联合治疗可能对高血压、高血脂和糖尿病患者有用。
Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE(-/-)) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE(-/-) mice. Diabetic ApoE(-/-) mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE(-/-) mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.
影响因子：
9.1
作者：
Lerman, Lilach O.;Textor, Stephen C.;Grande, Joseph P.
通讯作者：
Grande, Joseph P.
影响因子：
15.9
作者：
Lumeng, Carey N.;Bodzin, Jennifer L.;Saltiel, Alan R.
通讯作者：
Saltiel, Alan R.