Abstract | BACKGROUND: METHODS AND RESULTS: Endothelium-targeted overexpression of GTP cyclohydrolase 1 (GCH), the rate limiting enzyme in BH4 synthesis, increased levels of tetrahydrobiopterin (BH4), reduced endothelial superoxide, improved eNOS coupling, and reduced vein graft atherosclerosis in transgenic GCH/ ApoE-KO mice compared to ApoE-KO controls. Immunohistochemistry using anti-MAC-3 and MAC-1 antibody staining revealed a marked reduction in vein graft macrophage content, as did RT-PCR expression of macrophage marker CD68 mRNA levels in GCH/ ApoE-KO mice. When we investigated the potential mediators of this reduction, we discovered that mRNA and protein levels of MCP-1 (CCL2) but not RANTES (CCL5) were significantly reduced in GCH/ ApoE-KO aortic tissue. Consistent with this finding we found a decrease in CCR2-mediated, but not CCR5-mediated, chemotaxis in vascular tissue and plasma samples from GCH/ ApoE-KO animals. CONCLUSIONS:
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Authors | Ziad A Ali, Christina A Bursill, Gillian Douglas, Eileen McNeill, Marianna Papaspyridonos, Amy L Tatham, Jennifer K Bendall, Asim M Akhtar, Nicholas J Alp, David R Greaves, Keith M Channon |
Journal | Circulation
(Circulation)
Vol. 118
Issue 14 Suppl
Pg. S71-7
(Sep 30 2008)
ISSN: 1524-4539 [Electronic] United States |
PMID | 18824773
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Apolipoproteins E
- Ccr2 protein, mouse
- Chemokine CCL2
- Receptors, CCR2
- Superoxides
- Biopterin
- Nitric Oxide Synthase Type III
- GTP Cyclohydrolase
- sapropterin
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Topics |
- Animals
- Aorta
(metabolism)
- Apolipoproteins E
(deficiency)
- Atherosclerosis
(etiology, prevention & control)
- Biopterin
(analogs & derivatives, metabolism)
- Blood Vessels
(injuries)
- Carotid Arteries
(surgery)
- Chemokine CCL2
(metabolism)
- Chemotaxis
- Endothelium, Vascular
(metabolism)
- Female
- GTP Cyclohydrolase
(metabolism)
- Humans
- Hyperplasia
- Macrophages
(pathology)
- Male
- Mice
- Mice, Knockout
- Mice, Transgenic
- Nitric Oxide Synthase Type III
(metabolism)
- Receptors, CCR2
(metabolism)
- Superoxides
(metabolism)
- Tunica Intima
(pathology)
- Up-Regulation
- Vasculitis
(complications, prevention & control)
- Venae Cavae
(metabolism, pathology, transplantation)
- Wounds and Injuries
(complications)
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