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PO1-2-17

Absence of CCR3 receptor accelerates atherosclerosis in apoE-/- mice

[Speaker] Maria J Sanz:1
[Co-author] Aida Collado:1,2, Elena Domingo:1, Laura Perez-Alos:1, Patrice Marques:2, Eva Perello:2,3, Jose T Real:2,3,4,5, Laura Piqueras:2, Juan F Ascaso:2,3,4,5
1:Pharmacology, University of Valencia, Spain, 2:Institute of Health Research INCLIVA, Valencia, Spain, 3:Endocrinology and Nutrition Unit, University Clinic Hospital of Valencia, Valencia, Spain, 4:Department of Medicine, Faculty of Medicine, University of Valencia, Valencia, Spain, 5:CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, ISCIII, Spain

Introduction: Atherosclerosis is one of the leading causes of morbidity and mortality in Western countries and bears several histopathologic similarities to chronic inflammation. The early atherosclerotic lesion involves an inflammatory response consisting in the intimal accumulation of T lymphocytes and lipid-laden macrophages, and these events occur continuously throughout the entire atherogenic process. Eotaxin-1 (CCL11) expression has been detected in human and mouse atherosclerotic aortas (1,2), however, its role in the atherosclerotic lesion development remains elusive Objective: To evaluate the impact of an atherogenic diet in the lesion formation in apoE-/-; mice (apoE-/- CCR3+/+ mice) versus those lacking eotaxin receptor (CCR3, apoE-/- CCR3-/-). Materials and Methods: Two months old apoE-/- CCR3+/+ or apoE-/- CCR3-/- mice were subjected or not to an hypercholesterolemic diet (10.8% fat, 0.75% cholesterol) during two additional months. Lesion formation, collagen, necrotic core, vascular smooth muscle cells (VSMC), macrophage, T lymphocyte and eotaxin-1/CCL11 content were determined within the lesion through histological and immunohistochemical techniques. Results: ApoE-/- CCR3+/+ and apoE-/- CCR3-/- mice mice subjected to an hypercholesterolemic diet showed clear atherosclerotic lesion formation at the aortic sigmoid valve characterized by enhanced collagen, necrotic core, VSMC proliferation, macrophage and T lymphocyte infiltration than those subjected to a control diet. ApoE-/- CCR3-/- mice mice subjected to an atherogenic diet showed increased lesion formation, augmented collagen content and macrophage and T lymphocyte infiltration within the lesion than CCR3 expressing mice (apoE-/- CCR3+/+). Eotaxin-1 (CCL11) expression within the lesion of apoE-/- CCR3-/- mice in a hypercholesterolemic scenario was much higher than that detected in apoE-/- CCR3+/+ mice. Conclusion: These results suggest that the eotaxin-1 (CCL11)/CCR3 axis may exert a protective effect in the development of the atherosclerotic process.

References:
1. Haley, K. J., et al. (2000) Circulation 102, 2185-2189.
2. Kraaijeveld, A. O., et al. (2007) Curr Pharm Des 13, 1039-1052.

Funding: This work was supported by grants SAF2011-23777, SAF2014-57845R, CPII13/00025, PI15/00082, PIE15/00013, GVACOMP2014-006 and PROMETEO II/2013/014 from the Spanish Ministry of Economy and Competiveness, Carlos III Health Institute, the European Regional Development Fund and Generalitat Valenciana.

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