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

• Published in: Experimental & molecular medicine 2023, 55(0), , pp.426-442
• Main Authors: Cho, Dong Im, Ahn, Min Joo, Cho, Hyang Hee, Cho, Meeyoung, Jun, Ju Hee, Kang, Bo Gyeong, Lim, Soo Yeon, Yoo, Soo Ji, Kim, Mi Ra, Kim, Hyung-Seok, Lee, Su-Jin, Dat, Le Thanh, Lee, Changho, Kim, Yong Sook, Ahn, Youngkeun
• Format: Article
• Language: English
• Subjects: 14; 14/19; 14/28; 38/77; 631/250/256; 631/443/1338/2100; 631/443/592/75/593/2100; 64/60; 82; 82/51; 96/31; Angiopoietin; Animals; Apolipoprotein E; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - pathology; Biomedical and Life Sciences; Biomedicine; Blood vessels; Cardiovascular disease; Cardiovascular diseases; Cell activation; Cells, Cultured; Cerebral infarction; Down-Regulation; Inflammation; Inflammation - metabolism; KLF4 protein; Kruppel-Like Factor 4; Lipids; Macrophages; Medical Biochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Molecular Medicine; Muscle, Smooth, Vascular; Myocardial infarction; Myocytes, Smooth Muscle - metabolism; NAD(P)H oxidase; Patients; Phenotype; Phenotypes; Plaque, Atherosclerotic - pathology; Plaques; Proteins; Reactive oxygen species; Smooth muscle; Stem Cells; Vascular diseases; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-023-00937-x

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