Hyperlipidaemia impairs the circadian clock and physiological homeostasis of vascular smooth muscle cells via the suppression of Smarcd1

Siyu Chen; Yan Ding; Zhao Zhang; Han Wang; Chang Liu

doi:10.1002/path.4338

Hyperlipidaemia impairs the circadian clock and physiological homeostasis of vascular smooth muscle cells via the suppression of Smarcd1

J Pathol. 2014 Jun;233(2):159-69. doi: 10.1002/path.4338. Epub 2014 Mar 28.

Authors

Siyu Chen¹, Yan Ding, Zhao Zhang, Han Wang, Chang Liu

Affiliation

¹ Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China.

PMID: 24615205
DOI: 10.1002/path.4338

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.

Keywords: circadian clock; hyperlipidaemia; physiology; smarcd1; vascular smooth muscle cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ARNTL Transcription Factors / genetics
ARNTL Transcription Factors / metabolism
Animals
Aorta, Thoracic / metabolism
Aorta, Thoracic / pathology
CLOCK Proteins / genetics
CLOCK Proteins / metabolism
Cell Movement
Cell Proliferation
Cells, Cultured
Circadian Clocks* / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Diet, High-Fat
Disease Models, Animal
Down-Regulation
Enzyme Activation
Fatty Acids / metabolism
Homeostasis
Hyperlipidemias / etiology
Hyperlipidemias / genetics
Hyperlipidemias / metabolism*
Hyperlipidemias / pathology
Male
Mitogen-Activated Protein Kinases / metabolism
Muscle, Smooth, Vascular / metabolism*
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / metabolism*
Myocytes, Smooth Muscle / pathology
Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
RNA Interference
Rats
Rats, Sprague-Dawley
Signal Transduction
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic
Transfection

Substances

ARNTL Transcription Factors
DBP protein, rat
DNA-Binding Proteins
Fatty Acids
Nuclear Receptor Subfamily 1, Group F, Member 1
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, rat
Smarcd1 protein, rat
Transcription Factors
CLOCK Proteins
Clock protein, rat
Mitogen-Activated Protein Kinases