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17 Chemokine receptors as therapeutic targets in atherosclerosis: pharmacological characterisation of the human CCR5 knock-in mouse
  1. J J Maguire,
  2. P A Richards,
  3. R E Kuc,
  4. A P Davenport
  1. Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge, UK

Abstract

The CCR5 receptor and its ligands CCL3, CCL4 and CCL5 contribute to the initiation and progression of atherosclerosis. We have shown that smooth muscle CCR5 mediates vasoconstriction in human blood vessels that is antagonised by maraviroc, an anti-HIV drug. Maraviroc is reported to have low affinity for rodent CCR5. Therefore, our aim was to pharmacologically characterise vasoconstrictor responses to the selective CCR5 ligand CCL4 in the human CCR5 knock-in mouse, to determine whether human CCR5 is activated by the endogenous mouse ligand CCL4. Concentration-response curves to human CCL4, mouse CCL4 and control agonists phenylephrine and U-46619 were constructed in aorta from wild type and human CCR5 knock-in animals, set up in wire myographs. Responses were expressed as a per cent of the response to 100 mM KCl. Data were analysed to determine potency (pD2) and maximum response (EMAX %KCl). Values were expressed as mean±SEM and n-values are the number of mice. Responses to phenylephrine and U-46619 were not different between the two groups. The potency of human CCL4 was not different (knock-in pD2=9.59±0.23, n=10; wild type pD2=9.12±0.36, n=4) but the maximum response in the human CCR5 knock-in mouse aorta was significantly greater (EMAX=26.1±6.0%) than control (EMAX=8.0±2.3%) (p<0.05). Importantly, responses were obtained to the endogenous ligand, mouse CCL4, in the human knock-in animal (knock-in pD2 8.98±0.34, EMAX=16.4±5.4% n=8) as well as wild type (pD2=10.46±0.16, EMAX=14.3±8.2%, n=5). These data support the use of the human CCR5 knock-in mouse in further studies to evaluate the potential of maraviroc in atherosclerosis.

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