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

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.

Intermedin Inhibits the Ox-LDL–Induced Inflammation in RAW264.7 Cells by Affecting Fatty Acid–Binding Protein 4 Through the PKA Pathway

“…Our previous study showed that IMD ameliorates AS in ApoE null mice ( Zhang et al, 2012 ). Besides, a study suggested that IMD could prevent the atherosclerotic lesions progression by inhibiting ERS-CHOP–mediated apoptosis and inflammasome in macrophages ( Ren et al, 2021 ). However, it remains unclear whether other mechanisms are involved.…”

“…This reduces the expression of SIRT3 and UCP2, leading to an enhanced production of ROS and inflammatory responses ( Korbecki and Bajdak-Rusinek, 2019 ). In vitro study demonstrated that FABP4 knockout significantly reduced the expression of IL-1β, IL-6, TNF-α, and MCP-1 ( Fu et al, 2002 ; Ren et al, 2021 ). This is consistent with our results revealing that IMD reduced the generation of IL-6 and TNF-α in macrophages stimulated by ox-LDL, which might be another result ensuing the inhibition of FABP4.…”

Endoplasmic Reticulum Stress and Pathogenesis of Vascular Calcification

“…ERS stimulates the NLRP3 inflammasome activation through oxidative stress, NF-κB activation, and calcium homeostasis ( 86 ). Ren et al found that intermedin may attenuate the progression of atherosclerotic lesions and plaque susceptibility by inhibiting ERS-CHOP-mediated macrophage apoptosis and subsequent inflammation triggered by NLRP3 both in vivo and in vitro ( 87 ). Therefore, further studies are needed to elucidate the mechanisms of ERS-mediated and NLRP3 inflammasome-mediated VC.…”

Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases

“…Mechanistically, the antiaging factor SIRT1 mediated the inhibitory effects of IMD on aging-associated vascular calcification [ 88 ], while in renal failure-related vascular calcification, the protective role of IMD was mainly mediated by another antiaging factor, α -klotho [ 89 ]. Moreover, IMD 1-53 also inhibited the progression of atherosclerotic lesions, plaque vulnerability [ 90 ], and calcification [ 91 ] in ApoE-/- mice. Furthermore, our study demonstrated that IMD 1-53 protected against atherosclerosis and stabilized the lesions by inhibiting ERS-C/EBP-homologous protein- (CHOP-) mediated macrophage apoptosis, and the subsequent NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome triggered inflammation [ 90 , 91 ].…”