Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice
Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice
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奥美沙坦通过 DLL4/Notch1 通路激活减轻压力过载小鼠的心脏重塑
DOI：
10.1097/fjc.0b013e31827a0278
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发表时间：
2013-02
影响因子：
3
通讯作者：
Zou, Yunzeng
中科院分区：
文献类型：
--
作者：
You, Jieyun;Wu, Jian;Jiang, Guoliang;Guo, Jing;Wang, Shijun;Li, Lei;Ge, Junbo;Zou, Yunzeng
背景：Notch1信号控制心脏对应激的适应。因此，我们旨在验证广泛使用的血管紧张素II型1受体阻滞剂奥美沙坦是否通过delta-样配体4 (DLL4)/Notch1途径改善慢性压力过载小鼠的心脏重塑和功能障碍。方法：主动脉横缩引起心脏压力过载。将35只宽型C57BL/6J小鼠随机分为假手术组、TAC组、TAC +奥美沙坦组、TAC +奥美沙坦+ DAPT组（DAPT: &ggr；-分泌酶抑制剂、Notch信号抑制剂）。灌胃给予生理盐水（10 mL·kg−1·d−1）或相同体积的奥美沙坦液（3 mg·kg−1·d−1），腹膜注射DAPT （10 μ mol·kg−1·d−1）。治疗28 d后进行心脏血流动力学、超声心动图和组织学检查，并进行胎儿基因（ANP和SAA）表达的定量聚合酶链反应。western blot检测notch1相关蛋白和ERK1/2，酶联免疫吸附法检测血清血管紧张素II水平。结果：持续压力超载导致左心室肥厚、功能障碍、纤维化和微循环功能障碍，同时血管紧张素II、ERK1/2和胎儿基因表达上调。通过激活DLL4/Notch1，奥美沙坦降低左室肥厚和纤维化，保持心功能，改善毛细血管密度和冠状动脉灌注。这些疗效均被DAPT阻断Notch信号通路所抑制。结论：我们的研究发现了迄今为止未知的奥美沙坦通过激活DLL4/Notch1通路改善慢性压力过载小鼠心脏重塑和功能的药理机制，这可能是治疗高血压的新靶点。
Background: Notch1 signaling controls the cardiac adaptation to stress. We therefore aimed to validate whether olmesartan, a widely used angiotensin II type 1 receptor blocker, ameliorates cardiac remodeling and dysfunction via delta-like ligand 4 (DLL4)/Notch1 pathway in mice with chronic pressure overload. Methods: Cardiac pressure overload was produced by transverse aortic constriction (TAC). A total of 35 wide-type C57BL/6J mice were randomly divided into sham group, TAC group, TAC + olmesartan group, and TAC + olmsartan + DAPT group (DAPT: &ggr;-secretase inhibitor, Notch signaling inhibitor). Saline (10 mL·kg−1·d−1) or the same volume of olmesartan liquor (3 mg·kg−1 d−1) was administered by gavage, and DAPT (10 &mgr;mole·kg−1·d−1) by peritoneal injection. After 28 days of treatment, cardiac hemodynamics, echocardiography, and histology were evaluated, followed by quantitative polymerase chain reaction of fetal gene (ANP and SAA) expression. Notch1-related proteins and ERK1/2 were examined by western blot, and the serum level of angiotensin II was determined by means of enzyme-linked immunosorbent assay kits. Results: Persistent pressure overload-induced left ventricular hypertrophy, dysfunction, fibrosis, and microcirculation dysfunction, together with the upregulation of angiotensin II, ERK1/2, and fetal gene expression. By the activation of DLL4/Notch1, olmesartan decreased left ventricular hypertrophy and fibrosis, preserved cardiac function, and improved capillary density and coronary perfusion. All these curative effects were suppressed by pharmacological blockade of Notch signaling with DAPT. Conclusions: Our findings identify a heretofore unknown pharmacological mechanism that olmesartan improves cardiac remodeling and function via DLL4/Notch1 pathway activation in mice with chronic pressure overload, which may present a new therapeutic target for hypertension.
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影响因子：
1.6
作者：
Xu XH;Xu J;Xue L;Cao HL;Liu X;Chen YJ
通讯作者：
Chen YJ
影响因子：
--
作者：
Koshizaka M;Takemoto M;Sato S;Tokuyama H;Fujimoto M;Okabe E;Ishibashi R;Ishikawa T;Tsurutani Y;Onishi S;Mezawa M;He P;Honjo S;Ueda S;Saito Y;Yokote K
通讯作者：
Yokote K
压力过载引起的心脏肥大的发生需要 2 型瑞尼定受体
影响因子：
8.3
作者：
Shiojima, Ichiro;Wang, Yuqi;Komuro, Issei;Ge, Junbo
通讯作者：
Ge, Junbo
影响因子：
5.4
作者：
Agata, Jun;Ura, Nobuyuki;Shimamoto, Kazuaki
通讯作者：
Shimamoto, Kazuaki
影响因子：
5.3
作者：
Saraste, Antti;Kyto, Ville;Knuuti, Juhani
通讯作者：
Knuuti, Juhani