Intermedin1-53 attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages

Wei-Wei Lu,Yao Chen,Yan-Rong Yu,Jin-Ling Ren,Shi-Meng Liu,Mo-Zhi Jia,Ya-Rong Zhang,Chao-Shu Tang,Lin-Shuang Zhang,Yong-Fen Qi

doi:10.1038/s41419-021-03712-w

Abstract

Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE−/−) mice. Six-week IMD1-53 infusion significantly reduced atherosclerotic lesion size. Of note, IMD1-53 lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD1-53 administration prevented ERS activation in aortic lesions of ApoE−/− mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE−/− mice. IMD1-53 decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD1-53 infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.

Highlights

Atherosclerosis is a chronic inflammatory disease triggered by retention of lipids in large and medium-sized arteries[1,2,3]
Zhivotovsky apoptosis plays important roles in the rupture of atherosclerotic plaque. ● Endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis, and C/ EBP-homologous protein (CHOP), a branch of the ERS, is considered as an important molecular target for stabilizing atherosclerotic plaque by suppressing macrophage apoptosis. ● IMD, a newfound peptide of the calcitonin/ calcitonin gene-related peptide family, has been reported to alleviate many cardiovascular diseases by inhibiting ERS
We aimed to explore the role of IMD in promoting atherosclerotic plaque stability and, to test the hypothesis that inhibition of ERSCHOP-mediated macrophage apoptosis and subsequent inflammasome partly contributed to the plaque stabilizing effects of IMD

Summary

Introduction

Atherosclerosis is a chronic inflammatory disease triggered by retention of lipids in large and medium-sized arteries[1,2,3]. Rupture-prone plaques have increased plaque lipid content and large necrotic cores covered by thin fibrous caps, both intimal and adventitial inflammation, and increased apoptosis of vascular smooth muscle cells (VSMCs) and macrophages[7,8]. During the development of atherosclerotic plaques, macrophages can dominate both disease initiation and progression via the production and release of various cytokines and proteases[9]. Macrophage apoptosis occurs throughout all stages of atherosclerosis and plays important roles in plaque regression and plaque vulnerability. Defective phagocytic clearance of apoptotic macrophages may lead to a proinflammatory response by the inflammasome, accompanied by the generation of the necrotic core[9,10,11]. Increasing evidence suggests that advanced lesion macrophage apoptosis and inflammation is associated with necrotic core expansion and fibrous cap thinning[12,13,14]

Objectives

Methods

Results

Conclusion