Limits...
The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro.

Maguire JJ, Jones KL, Kuc RE, Clarke MC, Bennett MR, Davenport AP - Cardiovasc. Res. (2013)

Bottom Line: CCR5 and its ligands were expressed in normal and diseased coronary artery and saphenous vein and localized to medial and intimal smooth muscle, endothelial, and inflammatory cells. [(125)I]-CCL4 bound to venous smooth muscle with KD = 1.15 ± 0.26 nmol/L and density of 22 ± 9 fmol mg(-1) protein.Our data support a potential role for CCR5 in vasoconstriction and neointimal formation in vitro and imply that CCR5 chemokines may contribute to vascular remodelling and augmented vascular tone in human coronary artery and vein graft disease.The repurposing of maraviroc for the treatment of cardiovascular disease warrants further investigation.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Unit, Level 6 ACCI, Box 110 Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

ABSTRACT

Aims: The chemokine receptor CCR5 and its inflammatory ligands have been linked to atherosclerosis, an accelerated form of which occurs in saphenous vein graft disease. We investigated the function of vascular smooth muscle CCR5 in human coronary artery and saphenous vein, vascular tissues susceptible to atherosclerosis, and vasospasm.

Methods and results: CCR5 ligands were vasoconstrictors in saphenous vein and coronary artery. In vein, constrictor responses to CCL4 were completely blocked by CCR5 antagonists, including maraviroc. CCR5 antagonists prevented the development of a neointima after 14 days in cultured saphenous vein. CCR5 and its ligands were expressed in normal and diseased coronary artery and saphenous vein and localized to medial and intimal smooth muscle, endothelial, and inflammatory cells. [(125)I]-CCL4 bound to venous smooth muscle with KD = 1.15 ± 0.26 nmol/L and density of 22 ± 9 fmol mg(-1) protein.

Conclusions: Our data support a potential role for CCR5 in vasoconstriction and neointimal formation in vitro and imply that CCR5 chemokines may contribute to vascular remodelling and augmented vascular tone in human coronary artery and vein graft disease. The repurposing of maraviroc for the treatment of cardiovascular disease warrants further investigation.

Show MeSH

Related in: MedlinePlus

CCR5 receptor protein expression in (A) coronary atherosclerotic plaque and (B) thickened intima of failed saphenous vein graft. Co-localization (overlay: yellow/orange, arrow heads) of CCR5 immunoreactivity (green) with SMαA, CD68, and CD3-positive cells (red). Lack of fluorescence on omission of primary antibody shown for the vein graft. Scale bars: 30 μm. Relative levels of CCR5 mRNA in (C) saphenous vein (SV n = 5) and vein graft (SVG n = 4) and (D) donor (n = 5), DCM (n = 6) and ischaemic (IHD n = 5) myocardium. (E) Expression of CCL3 in saphenous vein graft: CCL3 immunoreactivity (green) co-localized in overlay (orange/yellow) with vWF, SMαA, CD68, and rarely CD3-positive cells (red). (F) Expression of CCL3, CCL4, and CCL5 mRNA was comparable in graft (SVG, n = 6) and normal vein (SV, n = 6). (G) In the left ventricle, CCL5 mRNA was significantly increased in IHD compared with donor (*P < 0.05, n = 6).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3928001&req=5

CVT333F5: CCR5 receptor protein expression in (A) coronary atherosclerotic plaque and (B) thickened intima of failed saphenous vein graft. Co-localization (overlay: yellow/orange, arrow heads) of CCR5 immunoreactivity (green) with SMαA, CD68, and CD3-positive cells (red). Lack of fluorescence on omission of primary antibody shown for the vein graft. Scale bars: 30 μm. Relative levels of CCR5 mRNA in (C) saphenous vein (SV n = 5) and vein graft (SVG n = 4) and (D) donor (n = 5), DCM (n = 6) and ischaemic (IHD n = 5) myocardium. (E) Expression of CCL3 in saphenous vein graft: CCL3 immunoreactivity (green) co-localized in overlay (orange/yellow) with vWF, SMαA, CD68, and rarely CD3-positive cells (red). (F) Expression of CCL3, CCL4, and CCL5 mRNA was comparable in graft (SVG, n = 6) and normal vein (SV, n = 6). (G) In the left ventricle, CCL5 mRNA was significantly increased in IHD compared with donor (*P < 0.05, n = 6).

Mentions: In atherosclerotic plaque of diseased coronary artery (Figure 5A) and thickened intima of failed saphenous vein graft (Figure 5B), CCR5 immunoreactivity was expressed in smooth muscle cells, macrophages, and to lesser extent CD3-positive cells. Compared with saphenous vein and donor myocardium, there was no significant alteration in CCR5 mRNA in saphenous vein graft or in hearts from patients transplanted for dilated cardiomyopathy (DCM) or ischaemic heart disease (IHD), the two most common diagnoses for cardiac transplantation32 (Figure 5C and D). There was no difference in receptor density between coronary artery media and intimal layers and media of saphenous vein and vein graft (P > 0.05, one-way analysis of variance followed by Bonferroni's multiple comparison test; Figure 3I). A similar cellular localization was obtained for CCL3, CCL4, and CCL5 as for CCR5 in coronary artery plaque and intima of failed vein graft (Figure 5E, and see Supplementary material online, Figure S13) and whereas levels of mRNA encoding CCR5 ligands were not different in normal and diseased saphenous vein (Figure 5F) comparison in donor compared with DCM or IHD ventricle showed highest expression of ligands in the IHD group, with CCL5 significantly increased compared with donors (Figure 5G, P < 0.05).Figure 5


The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro.

Maguire JJ, Jones KL, Kuc RE, Clarke MC, Bennett MR, Davenport AP - Cardiovasc. Res. (2013)

CCR5 receptor protein expression in (A) coronary atherosclerotic plaque and (B) thickened intima of failed saphenous vein graft. Co-localization (overlay: yellow/orange, arrow heads) of CCR5 immunoreactivity (green) with SMαA, CD68, and CD3-positive cells (red). Lack of fluorescence on omission of primary antibody shown for the vein graft. Scale bars: 30 μm. Relative levels of CCR5 mRNA in (C) saphenous vein (SV n = 5) and vein graft (SVG n = 4) and (D) donor (n = 5), DCM (n = 6) and ischaemic (IHD n = 5) myocardium. (E) Expression of CCL3 in saphenous vein graft: CCL3 immunoreactivity (green) co-localized in overlay (orange/yellow) with vWF, SMαA, CD68, and rarely CD3-positive cells (red). (F) Expression of CCL3, CCL4, and CCL5 mRNA was comparable in graft (SVG, n = 6) and normal vein (SV, n = 6). (G) In the left ventricle, CCL5 mRNA was significantly increased in IHD compared with donor (*P < 0.05, n = 6).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928001&req=5

CVT333F5: CCR5 receptor protein expression in (A) coronary atherosclerotic plaque and (B) thickened intima of failed saphenous vein graft. Co-localization (overlay: yellow/orange, arrow heads) of CCR5 immunoreactivity (green) with SMαA, CD68, and CD3-positive cells (red). Lack of fluorescence on omission of primary antibody shown for the vein graft. Scale bars: 30 μm. Relative levels of CCR5 mRNA in (C) saphenous vein (SV n = 5) and vein graft (SVG n = 4) and (D) donor (n = 5), DCM (n = 6) and ischaemic (IHD n = 5) myocardium. (E) Expression of CCL3 in saphenous vein graft: CCL3 immunoreactivity (green) co-localized in overlay (orange/yellow) with vWF, SMαA, CD68, and rarely CD3-positive cells (red). (F) Expression of CCL3, CCL4, and CCL5 mRNA was comparable in graft (SVG, n = 6) and normal vein (SV, n = 6). (G) In the left ventricle, CCL5 mRNA was significantly increased in IHD compared with donor (*P < 0.05, n = 6).
Mentions: In atherosclerotic plaque of diseased coronary artery (Figure 5A) and thickened intima of failed saphenous vein graft (Figure 5B), CCR5 immunoreactivity was expressed in smooth muscle cells, macrophages, and to lesser extent CD3-positive cells. Compared with saphenous vein and donor myocardium, there was no significant alteration in CCR5 mRNA in saphenous vein graft or in hearts from patients transplanted for dilated cardiomyopathy (DCM) or ischaemic heart disease (IHD), the two most common diagnoses for cardiac transplantation32 (Figure 5C and D). There was no difference in receptor density between coronary artery media and intimal layers and media of saphenous vein and vein graft (P > 0.05, one-way analysis of variance followed by Bonferroni's multiple comparison test; Figure 3I). A similar cellular localization was obtained for CCL3, CCL4, and CCL5 as for CCR5 in coronary artery plaque and intima of failed vein graft (Figure 5E, and see Supplementary material online, Figure S13) and whereas levels of mRNA encoding CCR5 ligands were not different in normal and diseased saphenous vein (Figure 5F) comparison in donor compared with DCM or IHD ventricle showed highest expression of ligands in the IHD group, with CCL5 significantly increased compared with donors (Figure 5G, P < 0.05).Figure 5

Bottom Line: CCR5 and its ligands were expressed in normal and diseased coronary artery and saphenous vein and localized to medial and intimal smooth muscle, endothelial, and inflammatory cells. [(125)I]-CCL4 bound to venous smooth muscle with KD = 1.15 ± 0.26 nmol/L and density of 22 ± 9 fmol mg(-1) protein.Our data support a potential role for CCR5 in vasoconstriction and neointimal formation in vitro and imply that CCR5 chemokines may contribute to vascular remodelling and augmented vascular tone in human coronary artery and vein graft disease.The repurposing of maraviroc for the treatment of cardiovascular disease warrants further investigation.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Unit, Level 6 ACCI, Box 110 Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

ABSTRACT

Aims: The chemokine receptor CCR5 and its inflammatory ligands have been linked to atherosclerosis, an accelerated form of which occurs in saphenous vein graft disease. We investigated the function of vascular smooth muscle CCR5 in human coronary artery and saphenous vein, vascular tissues susceptible to atherosclerosis, and vasospasm.

Methods and results: CCR5 ligands were vasoconstrictors in saphenous vein and coronary artery. In vein, constrictor responses to CCL4 were completely blocked by CCR5 antagonists, including maraviroc. CCR5 antagonists prevented the development of a neointima after 14 days in cultured saphenous vein. CCR5 and its ligands were expressed in normal and diseased coronary artery and saphenous vein and localized to medial and intimal smooth muscle, endothelial, and inflammatory cells. [(125)I]-CCL4 bound to venous smooth muscle with KD = 1.15 ± 0.26 nmol/L and density of 22 ± 9 fmol mg(-1) protein.

Conclusions: Our data support a potential role for CCR5 in vasoconstriction and neointimal formation in vitro and imply that CCR5 chemokines may contribute to vascular remodelling and augmented vascular tone in human coronary artery and vein graft disease. The repurposing of maraviroc for the treatment of cardiovascular disease warrants further investigation.

Show MeSH
Related in: MedlinePlus