| Abstract | Peripherally produced corticotrophin-releasing hormone (CRH) is a strong proinflammatory factor involved in many inflammatory diseases. However, to date, there is no evidence about the action of CRH on atherosclerosis, a chronic disease characterized by inflammatory reactions. In this study we observed the effect of CRH on atherosclerosis in low-density lipoprotein receptor-deficient (LDLr-/-) mice. Twelve-week-old, male LDLr-/- mice were subcutaneously injected with CRH (10microg/kg) or vehicle once a day for 8 weeks. The results indicated aortic atherosclerotic lesions were larger (P<0.01) in CRH-treated mice than those in untreated mice. CRH significantly up-regulated the expression of both protein and mRNA for vascular cell adhesion molecule-1 (VCAM-1), together with a markedly increased activation of nuclear factor kappa B (NF-kappaB) in aortas. In addition, the blood lipid levels were not influenced by CRH subcutaneous injection. The significant proatherogenic effect of CRH in LDLr-/- mice was largely attenuated by selective CRH receptor 1 (CRHR1) antagonist NBI27914 but not by specific CRH receptor 2 (CRHR2) antagonist antisauvagine-30 (anti-Svg-30). Meanwhile, both the enhanced expression of VCAM-1 and increased activation of NF-kappaB induced by CRH in aortas of LDLr-/- mice were also largely suppressed by NBI27914, whereas these inhibitory effects were not observed in anti-Svg-30 group. Taken together, these findings indicated that CRH may accelerate atherosclerosis progression in LDLr-/- mice via CRHR1. The enhanced VCAM-1 expression which probably resulted from increased activation of NF-kappaB induced by CRH, may be one of the important molecular mechanisms by which CRH accelerates atherosclerosis. This study provides a new insight into the effect of CRH on atherosclerosis and suggests a potential target for the prevention and treatment of atherosclerosis. |
| Authors | Yuqing Wu, Rongjian Zhang, Chenghua Zhou, Youhua Xu, Xiaowei Guan, Jue Hu, Yinyan Xu, Shengnan Li
(Affiliation: Department of Pharmacology, Nanjing Medical University, PR China.)
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| Journal | Atherosclerosis
(Atherosclerosis)
Vol. 203
Issue 2
Pg. 360-70
(Apr 2009)
ISSN: 1879-1484 [Electronic] Ireland |
| PMID | 18640679
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- 2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine
- Aniline Compounds
- Cell Adhesion Molecules
- NF-kappa B p50 Subunit
- Peptide Fragments
- Pyrimidines
- Receptors, LDL
- Transcription Factors
- Vascular Cell Adhesion Molecule-1
- antisauvagine 30
- Nfkb1 protein, mouse
- Corticotropin-Releasing Hormone
|
| Topics |
- Aniline Compounds
(pharmacology)
- Animals
- Atherosclerosis
(blood, pathology)
- Cell Adhesion Molecules
(metabolism)
- Corticotropin-Releasing Hormone
(blood)
- Gene Expression Regulation
- Inflammation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- NF-kappa B p50 Subunit
(metabolism)
- Peptide Fragments
(pharmacology)
- Pyrimidines
(pharmacology)
- Receptors, LDL
(genetics)
- Transcription Factors
(metabolism)
- Vascular Cell Adhesion Molecule-1
(biosynthesis)
|
