ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation

Abstract

Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe−/− mice and analyzed the atherosclerotic lesion size, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the control group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFα-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in the attenuation of KLF4-mediated SMC phenotypic changes. We showed that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than AMI patients with lower levels of ANGPTL4 (p < 0.05). Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques.

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

“…Moreover, in mice, Ang-2 showed increased expression in lesions with intraplaque hemorrhage compared to regions of the lesions without [202]. From other experiments in mice, when Ang-4 protein was injected twice a week into atherosclerotic ApoE−/−mice, Ang-4 reduced atherosclerotic plaque size and vascular inflammation and inhibited atherogenesis [203]. Another study showed that genetic ablation of Ang-4 in adipose tissue results in enhanced plasma lipoprotein lipase (LPL) activity, the rapid clearance of circulating triacylglycerols, increased lipolysis and fatty acid oxidation, and de-creased synthesis, suggesting that a lack of Ang-4 in adipose tissue enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis.…”

Correlation between the serum FABP4, ANGPTL3, and ANGPTL4 levels and coronary artery disease

“…In vitro studies have shown that ANGPTL4 can alleviate apoptosis and oxidative stress of bone marrow mesenchymal stem cells induced by hypoxia and alleviate myocardial damage in rats with myocardial infarction 37 . The intervention of ANGPTL4 in AS mice can reduce the proliferation of vascular smooth muscle cells and the progression of atherosclerotic plaque 38 . It has been observed in mice with acute myocardial infarction that the elevated ANGPTL4 level is caused by hypoxia, which has a protective effect on the heart and can even be used to predict the prognosis of the disease 39 .…”

“…37 The intervention of ANGPTL4 in AS mice can reduce the proliferation of vascular smooth muscle cells and the progression of atherosclerotic plaque. 38 It has been observed in mice with acute myocardial infarction that the elevated ANGPTL4 level is caused by hypoxia, which has a protective effect on the heart and can even be used to predict the prognosis of the disease. 39 Since ANGPTL4 also plays a role in inhibiting inflammation, its role and mechanism in CAD…”

Chronotherapy involving rosiglitazone regulates the phenotypic switch of vascular smooth muscle cells by shifting the phase of TNF-α rhythm through triglyceride accumulation in macrophages

“…Vascular smooth muscle cells (VSMCs) drive cardiovascular disease (CVD) via phenotype switch [ [1] , [2] ]. It is widely recognized that controlling the phenotypic transition of VSMCs is beneficial for treating CVDs [ [3] , [4] ]. In response to stress or vascular injury, contractile VSMCs can switch to a less differentiated state (synthetic phenotype) to acquire the proliferative, migratory, and synthetic capabilities for tissue reparation [ [5] , [6] ].…”