Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4.
Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4.
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DOI：
10.5551/jat.27292
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发表时间：
2015-08-26
影响因子：
4.4
通讯作者：
Matsuzaki M
中科院分区：
文献类型：
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作者：
Matsuda S;Umemoto S;Yoshimura K;Itoh S;Murata T;Fukai T;Matsuzaki M
血管紧张素II（AngII）产生活性氧（ROS），从而促进心脏肥大和随后的心力衰竭的发展，并刺激单核细胞趋化蛋白-1（MCP-1）的表达。此外，Toll样受体4（TLR 4）参与MCP-1的上调。为了阐明TLR 4是否参与AngII刺激引起的心功能不全的发生，我们研究了TLR 4对AngII诱导的高血压小鼠氧化应激、MCP-1表达和心功能不全的影响。TLR 4缺陷型（Tlr 41 PS-d）和野生型（WT）小鼠随机分成用AngII、去甲肾上腺素（NE）或亚降压剂量的AngII受体阻断剂厄贝沙坦（IRB）和AngII治疗两周的组。在WT和T1 r4 lps-d小鼠中，与对照组相比，所有药物治疗组中AngII和NE相似地增加收缩压（p< 0.05）。在WT小鼠中，AngII诱导心脏肥大以及心肌内动脉的血管重构和血管周围纤维化以及心脏中的单核细胞/巨噬细胞浸润（P<0.05）。AngII治疗组左室舒张功能降低，左室收缩末期内径增大（P<0.05），NADPH氧化酶活性、ROS含量和MCP-1表达增加5倍（P<0.05）。相反，Tlr 4lps-d小鼠显示AngII对这些指标的影响很小。在WT小鼠中，与单独用AngII治疗的小鼠相比，IRB治疗逆转了这些变化。NE对WT或T1 r4 lps-d小鼠的任何指数几乎没有影响。TLR 4可能参与氧化应激增加、选择性激活MCP-1表达以及AngII诱导的高血压病例中观察到的心脏肥大和功能障碍的潜在过程。
Angiotensin II (AngII) produces reactive oxygen species (ROS), thus contributing to the development of cardiac hypertrophy and subsequent heart failure, and stimulates the expression of monocyte chemoattractant protein-1 (MCP-1). In addition, Toll-like receptor 4 (TLR4) is involved in the upregulation of MCP-1. In order to clarify whether TLR4 is involved in the onset of cardiac dysfunction caused by AngII stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with AngII-induced hypertension. TLR4-deficient (Tlr4lPS-d) and wild-type (WT) mice were randomized into groups treated with AngII, norepinephrine (NE) or a subdepressor dose of the AngII receptor blocker irbesartan (IRB) and Angll for two weeks. AngII and NE similarly increased systolic blood pressure in all drug-treated groups compared to that observed in the control group among both WT and T1r4lps-d mice (p< 0.05). In the WT mice, AngII induced cardiac hypertrophy as well as vascular remodeling and perivascular fibrosis of the intramyocardial arteries and monocyte/macrophage infiltration in the heart (P<0.05). Furthermore, AngII treatment decreased the left ventricular diastolic function and resulted in a greater left ventricular end-systolic dimension (P<0.05) in addition to producing a five-fold increase in the NADPH oxidase activity, ROS content and MCP-1 expression (P<0.05). In contrast, the Tlr4lps-d mice showed little effects of AngII on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with AngII alone. NE produced little effect on any of the indices in either the WT or T1r4lps-d mice. TLR4 may be involved in the processes underlying the increased oxidative stress, selectively activated MCP-1 expression and cardiac hypertrophy and dysfunction seen in cases of AngII-induced hypertension.