The role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in angiotensin II-induced macrophage apoptosis and vulnerable plaque formation
The role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in angiotensin II-induced macrophage apoptosis and vulnerable plaque formation
复制标题
单核细胞趋化蛋白诱导蛋白1（MCPIP1）在血管紧张素II诱导巨噬细胞凋亡和易损斑块形成中的作用
DOI：
10.1016/j.bbrc.2019.05.145
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发表时间：
2019
影响因子：
3.1
通讯作者：
Zhou Juan
中科院分区：
文献类型：
--
作者：
Shu Shan;Zhang Yan;Li Wenyuan;Wang Lijun;Wu Yue;Yuan Zuyi;Zhou Juan
动脉粥样硬化斑块破裂是急性冠状动脉综合征（ACS）的主要原因。血管紧张素II（AngII）和巨噬细胞凋亡参与动脉粥样硬化的发病机制。然而，其潜在机制仍不清楚。我们的目的是解决单核细胞趋化蛋白诱导蛋白1（MCPIP 1）在血管紧张素II诱导的巨噬细胞凋亡和易损斑块形成的作用。在小鼠腹腔巨噬细胞中，Ang II促进内质网（ER）应激依赖的巨噬细胞凋亡。Ang Ⅱ通过激活p38丝裂原活化蛋白激酶（p38 MAPK），显著上调MCPIP 1的表达。用MCPIP 1 shRNA处理下调ER应激相关蛋白，减少Ang II诱导的巨噬细胞凋亡。Ang II还激活巨噬细胞中的AMP活化蛋白激酶（AMPK）信号。AMPK的抑制通过抑制p38 MAPK/MCPIP 1/ER应激途径减少巨噬细胞凋亡。此外，用氯沙坦阻断Ang II 1型受体（AT 1 R）可有效抑制Ang II诱导的巨噬细胞凋亡和AMPK/p38 MAPK/MCPIP 1/ER通路的激活。在小鼠动脉粥样硬化易损斑块模型中，氯沙坦抑制动脉粥样硬化的进展，并将易损斑块转化为更稳定的表型。氯沙坦还能显著降低损伤区CD 68 +TUNEL+、CD 68 + MCPIP 1+、CD 68 + p-eIF 2 α+和CD 68 +CHOP+细胞的数量。总之，Ang II通过其受体AT 1 R在巨噬细胞中通过AMPK/p38 MAPK/MCPIP 1/ER应激途径促进巨噬细胞凋亡，这可能有助于易损斑块的形成。我们的研究阐明了MCPIP 1在Ang II诱导的巨噬细胞凋亡和斑块不稳定性中的新的调节作用，为预防ACS提供了潜在的治疗靶点。
Atherosclerotic plaque rupture is the main cause of acute coronary syndrome (ACS). Angiotensin II (Ang II) and macrophage apoptosis are involved in the pathogenesis of atherosclerosis. However, the underlying mechanisms remain unclear. We aimed to address the role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in Ang II-induced macrophage apoptosis and vulnerable plaque formation. In mouse peritoneal macrophages, Ang II promoted endoplasmic reticulum (ER) stress-dependent macrophage apoptosis. Ang II markedly upregulated the expression of MCPIP1 via activating p38 mitogen-activated protein kinase (p38 MAPK). Treatment with MCPIP1 shRNA downregulated ER stress-related proteins and decreased macrophage apoptosis induced by Ang II. Ang II also activated the AMP-activated protein kinase (AMPK) signaling in macrophages. Inhibition of AMPK reduced macrophage apoptosis by inhibiting the p38 MAPK/MCPIP1/ER stress pathway. Furthermore, blocking the Ang II type 1 receptor (AT1R) with losartan effectively inhibited Ang II-induced macrophage apoptosis and AMPK/p38 MAPK/MCPIP1/ER pathway activation. In the atherosclerotic vulnerable plaque model in mice, losartan inhibited the progression of atherosclerosis and transformed vulnerable plaque into a more stable phenotype. Moreover, losartan markedly decreased the number of CD68+TUNEL+, CD68+MCPIP1+, CD68+p-eIF2α+and CD68+CHOP+cells in the lesion area. Taken together, Ang II promotes macrophage apoptosis via the AMPK/p38 MAPK/MCPIP1/ER stress pathway in macrophages via its receptor AT1R, which may contribute to vulnerable plaque formation. Our study clarifies a novel regulatory role of MCPIP1 in Ang II-induced macrophage apoptosis and plaque instability, providing a potential therapeutic target for prevention of ACS.