title: Hyperlipidaemia impairs the circadian clock and physiological homeostasis of vascular smooth muscle cells via the suppression of Smarcd1.
abstract: Many mammalian physiological processes show diurnal oscillation and are controlled by a circadian clock. Disruption of the circadian clock has been implicated in the pathogenesis of cardiovascular disorders, but the mechanism through which clock and vessel function are integrated is unclear. Here we show that the rhythmicity of key clock genes and Smarcd1, a member of the SWI/SNF chromatin remodelling complex family, is suppressed in the layer of vascular smooth muscle cells (VSMCs) of the thoracic aorta of hyperlipidaemic rats fed a high-fat diet (HFD). Smarcd1 stimulates the transcription of clock genes, notably bmal1, through co-activation of the nuclear orphan receptor RORα in VSMCs. The co-activation of Smarcd1 and RORα is dependent on the mediation of PGC-1α, a transcriptional co-activator. Pathophysiologically, Smarcd1 inhibits VSMC proliferation and migration by blocking cell cycle re-entry and via the activation of kinase signalling pathways. Our results demonstrate that Smarcd1 is a critical node integrating the circadian clock and VSMC physiological homeostasis.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis; D006949:Hyperlipidemias / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D056930:ARNTL Transcription Factors; C485975:DBP protein, rat; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; C000589389:Smarcd1 protein, rat; D014157:Transcription Factors; D056926:CLOCK Proteins; C538945:Clock protein, rat; D020928:Mitogen-Activated Protein Kinases
keywords: circadian clock; hyperlipidaemia; physiology; smarcd1; vascular smooth muscle cells