The role of circadian clock gene BMAL1 in vascular proliferation

• Published in: European journal of pharmacology Vol. 872; p. 172924
• Main Authors: Takaguri, Akira, Sasano, Jun, Akihiro, Oomiya, Satoh, Kumi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.04.2020
• Subjects: Animals; ARNTL Transcription Factors - antagonists & inhibitors; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Atherosclerosis - drug therapy; Atherosclerosis - pathology; Becaplermin - pharmacology; BMAL1; Carotid Arteries - pathology; Carotid Artery Injuries - pathology; Carotid Artery Injuries - physiopathology; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cells, Cultured; Circadian Rhythm - physiology; Disease Models, Animal; Egr-1; Gene Knockdown Techniques; Humans; Male; MAP Kinase Signaling System - drug effects; Mice; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - pathology; PDGF-BB; Primary Cell Culture; Rats; Reactive Oxygen Species - metabolism; Vascular Remodeling - drug effects; Vascular Remodeling - physiology; Vascular smooth muscle cells; Cell proliferation; Egr-1; BMAL1; Vascular smooth muscle cells; PDGF-BB
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.172924

Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, is implicated in the development of cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysms. However, the role of BMAL1 in vascular proliferation associated with vascular remodeling is unknown. In the present study, we investigated the mechanisms underlying BMAL1 expression in vascular smooth muscle cells (VSMCs) and the role of BMAL1 in VSMC proliferation. BMAL1 expression significantly increased in injured carotid arteries in C57BL/6J mice and platelet-derived growth factor (PDGF)-BB-stimulated VSMC cultures. Pretreatment with diphenyleneiodonium (an NADPH oxidase inhibitor) and U0126 or PD98059 (MEK Inhibitors) inhibited PDGF-BB-induced BMAL1 expression in a dose-dependent manner in VSMCs. In addition, the knockdown of early growth factor protein-1 (Egr-1) significantly inhibited PDGF-BB-induced BMAL1 mRNA or protein expression in VSMCs, and the knockdown of BMAL1 significantly decreased PDGF-BB-induced cell proliferation and extracellular signal-regulated kinase (ERK) phosphorylation but not Akt phosphorylation in VSMCs. The results demonstrate that PDGF-BB up-regulates BMAL1 expression through reactive oxygen species/ERK/Egr-1 pathways and that BMAL1 is involved in PDGF-BB-induced cell proliferation partially through ERK in VSMCs. Thus, BMAL1 may be a novel therapeutic target for the treatment of atherosclerosis including vascular remodeling.