Phosphorylation of Nonmuscle Myosin Light Chain Promotes Endothelial Injury in Hyperlipidemic Rats Through a Mechanism Involving Downregulation of Dimethylarginine Dimethylaminohydrolase 2

Autor: Jie-Jie Zhang, Lian-Sheng Li, Zhi-Chun Yang, Jun-Lin Jiang, Jun Peng, Qi-Lin Ma, Xiu-Ju Luo, Yan Wu, Ting-Bo Li, Wei-Qi Liu
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Arginine
030204 cardiovascular system & hematology
Rats
Sprague-Dawley
chemistry.chemical_compound
0302 clinical medicine
Pharmacology (medical)
Phosphorylation
Endothelial dysfunction
Aorta
Cells
Cultured
Regulation of gene expression
Lipids
Lipoproteins
LDL
Vasodilation
Biochemistry
Signal transduction
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.medical_specialty
Myosin Light Chains
Myosin light-chain kinase
Aortic Diseases
Down-Regulation
Hyperlipidemias
Nitric Oxide
Amidohydrolases
Nitric oxide
03 medical and health sciences
Downregulation and upregulation
Internal medicine
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Myosin-Light-Chain Kinase
Protein Kinase Inhibitors
Pharmacology
business.industry
Endothelial Cells
Atherosclerosis
medicine.disease
Disease Models
Animal
030104 developmental biology
Endocrinology
chemistry
business
Asymmetric dimethylarginine
Zdroj: Journal of Cardiovascular Pharmacology and Therapeutics. 21:536-548
ISSN: 1940-4034
1074-2484
DOI: 10.1177/1074248416634465
Popis: Suppression of dimethylarginine dimethylaminohydrolase (DDAH) activation is related to endothelial dysfunction in hyperlipidemia, and nonmuscle myosin regulatory light chain (nmMLC20) has been show to exert transcriptional function in regulation of gene expression. This study aims to explore whether the suppression of DDAH activation promotes endothelial injury under the condition of hyperlipidemia and whether nmMLC20 can regulate DDAH expression in a phosphorylation-dependent manner. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial injury, accompanied by an elevation in myosin light chain kinase (MLCK) activity, phosphorylated nmMLC20 (p-nmMLC20) level, and asymmetric dimethylarginine (ADMA) content as well as a reduction in DDAH2 expression, DDAH activity, and nitric oxide (NO) content. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL; 100 μg/mL) for 24 hours to establish a cellular injury model in vitro. Consistent with the finding in vivo, ox-LDL induced HUVECs injury (apoptosis and necrosis) concomitant with an increase in MLCK activity, p-nmMLC20 level (in total or nuclear proteins), and ADMA content as well as a reduction in DDAH2 expression, DDAH activity, and NO content; these phenomena were attenuated by MLCK inhibitor. Either in hyperlipidemic rats or in ox-LDL-treated HUVECs, there was not significant change in DDAH1 expression. Based on these observations, we conclude that the suppression of DDAH2 expression might account for, at least partially, the vascular endothelial dysfunction in hyperlipidemia, and nmMLC20 plays a role in suppression of DDAH2 expression in a phosphorylation-dependent manner.
Databáze: OpenAIRE
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