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

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 alpha-SMA(+), SM22 alpha(+), 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 Kruppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of alpha-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNF alpha-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. Cardiovascular disease: Stopping and stabilizing atherosclerotic plaquesTreatment with a protein that stabilizes existing plaques within blood vessels could help reduce the risk of future cardiovascular events in patients with atherosclerosis. These plaques arise in part from a change in the behavior of the muscle cells within the walls of the blood vessels, which leads to the accumulation of lipids and other biomolecules and creates conditions that can ultimately result in a heart attack or stroke. Researchers led by Youngkeun Ahn and Yong Sook Kim at Chonnam National University Hospital, Gwangju, South Korea, have shown that they can counter this process in a mouse model of atherosclerosis by treatment with a protein called ANGPTL4. This molecule keeps vascular muscle cells in a state that prevents further plaque formation, while stabilizing existing plaques and countering the inflammatory processes that can further accelerate the cardiovascular disease.

Automated summary

Atherosclerosis is a vascular disease caused by chronic inflammation, and it is the leading cause of death. The protein ANGPTL4 has been shown to promote cardiac repair by suppressing pathological inflammation. In this study, it was found that ANGPTL4 protein can reduce the size of atherosclerotic plaques, decrease vascular inflammation, and improve plaque stability. This research provides a novel therapeutic strategy for preventing and treating atherosclerosis.