SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. 10; pp. 2460 - 2473
• Main Authors: Nishino, Tomohiro, Horie, Takahiro, Baba, Osamu, Sowa, Naoya, Hanada, Ritsuko, Kuwabara, Yasuhide, Nakao, Tetsushi, Nishiga, Masataka, Nishi, Hitoo, Nakashima, Yasuhiro, Nakazeki, Fumiko, Ide, Yuya, Koyama, Satoshi, Kimura, Masahiro, Nagata, Manabu, Yoshida, Kazumichi, Takagi, Yasushi, Nakamura, Tomoyuki, Hasegawa, Koji, Miyamoto, Susumu, Kimura, Takeshi, Ono, Koh
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.10.2018
• Subjects: Aged; Aged, 80 and over; Animals; Apoptosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Bone Marrow Transplantation; Case-Control Studies; Cholesterol, HDL - blood; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Intestinal Absorption; Macrophages - metabolism; Macrophages - pathology; Male; Membrane Microdomains - metabolism; Mice, Inbred C57BL; Mice, Knockout, ApoE; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Phenotype; Plaque, Atherosclerotic; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Triglycerides - blood; atherosclerosis; microRNAs; cholesterol, HDL; bone marrow transplantation; lipid metabolism
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.118.311409

OBJECTIVE—Atherosclerosis is a common disease caused by a variety of metabolic and inflammatory disturbances. MicroRNA (miR)-33a within SREBF2 (sterol regulatory element-binding factor 2) is a potent target for treatment of atherosclerosis through regulating both aspects; however, the involvement of miR-33b within SREBF1 remains largely unknown. Although their host genes difference could lead to functional divergence of miR-33a/b, we cannot dissect the roles of miR-33a/b in vivo because of lack of miR-33b sequences in mice, unlike human. APPROACH AND RESULTS—Here, we analyzed the development of atherosclerosis using miR-33b knock-in humanized mice under apolipoprotein E–deficient background. MiR-33b is prominent both in human and mice on atheroprone condition. MiR-33b reduced serum high-density lipoprotein cholesterol levels and systemic reverse cholesterol transport. MiR-33b knock-in macrophages showed less cholesterol efflux capacity and higher inflammatory state via regulating lipid rafts. Thus, miR-33b promotes vulnerable atherosclerotic plaque formation. Furthermore, bone marrow transplantation experiments strengthen proatherogenic roles of macrophage miR-33b. CONCLUSIONS—Our data demonstrated critical roles of SREBF1-miR-33b axis on both lipid profiles and macrophage phenotype remodeling and indicate that miR-33b is a promising target for treating atherosclerosis.