Abstract | BACKGROUND: METHODS AND RESULTS: We investigated the role of nmMLCK in the development of atherosclerotic lesions in apolipoprotein E-deficient ( apoE(-/-)) mice fed an atherogenic diet for 12 weeks. Histopathological examination demonstrated that nmMLCK deficiency ( apoE(-/-)nmmlck(-/-)) reduced the size of aortic lesions by 53%, lipid contents by 44%, and macrophage deposition by 40%. Western blotting and reverse-transcription polymerase chain reaction revealed the expression of nmMLCK in aortic endothelial cells and peripheral blood monocytes. Measurements of transendothelial electric resistance indicated that nmMLCK deficiency attenuated endothelial barrier dysfunction caused by thrombin, oxidized low-density lipoprotein, and tumor necrosis factor α. In monocytes, nmMLCK deficiency reduced their migration in response to the chemokine monocyte chemoattractant protein-1. Further mechanistic studies showed that nmMLCK acted through both myosin light chain phosphorylation-coupled and -uncoupled pathways; the latter involved Rous sacracoma virus homolog genes-encoded tyrosine kinases (Src) signaling. Moreover, depletion of Src via gene silencing, site-specific mutagenesis, or pharmacological inhibition of Src greatly attenuated nmMLCK-dependent endothelial barrier dysfunction and monocyte migration. CONCLUSIONS:
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Authors | Chongxiu Sun, Mack H Wu, Sarah Y Yuan |
Journal | Circulation
(Circulation)
Vol. 124
Issue 1
Pg. 48-57
(Jul 05 2011)
ISSN: 1524-4539 [Electronic] United States |
PMID | 21670231
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Apolipoproteins E
- Collagen
- src-Family Kinases
- Myosin-Light-Chain Kinase
- non-muscle myosin light-chain kinase, mouse
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Topics |
- Animals
- Aorta
(pathology)
- Apolipoproteins E
(deficiency, genetics, physiology)
- Atherosclerosis
(pathology, physiopathology, prevention & control)
- Cell Movement
(physiology)
- Cells, Cultured
- Collagen
(metabolism)
- Disease Models, Animal
- Endothelium, Vascular
(metabolism, pathology, physiopathology)
- Lipid Metabolism
(physiology)
- Macrophages
(pathology)
- Male
- Mice
- Mice, Knockout
- Monocytes
(pathology, physiology)
- Myosin-Light-Chain Kinase
(deficiency, genetics, physiology)
- Phosphorylation
- Signal Transduction
(physiology)
- Tunica Intima
(metabolism)
- src-Family Kinases
(physiology)
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