Enhanced expression of vascular cell adhesion molecule-1 by corticotrophin-releasing hormone contributes to progression of atherosclerosis in LDL receptor-deficient mice.
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.
Wu
Yuqing
Y
Department of Pharmacology, Nanjing Medical University, PR China.
Zhang
Rongjian
R
Zhou
Chenghua
C
Xu
Youhua
Y
Guan
Xiaowei
X
Hu
Jue
J
Xu
Yinyan
Y
Li
Shengnan
S
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000097:blood*; D005786:Gene Expression Regulation; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D000814:Aniline Compounds; D015815:Cell Adhesion Molecules; D052002:NF-kappa B p50 Subunit; D010446:Peptide Fragments; D011743:Pyrimidines; D011973:Receptors, LDL; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; C116607:antisauvagine 30; C073701:Nfkb1 protein, mouse; D003346:Corticotropin-Releasing Hormone