P2Y 6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice
| Autor: | Dennis Wolf, Cemil Korcan Ayata, Timoteo Marchini, Nathaly Anto Michel, Natalie Hoppe, Lisa Schulte, Alexander Peikert, Sanja Cicko, Christoph Bode, Jochen Reinöhl, Constantin von zur Mühlen, Marco Idzko, Sonja Hergeth, Peter Stachon, Andreas Zirlik, Bianca Dufner, Melanie Grimm |
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| Rok vydání: | 2014 |
| Předmět: |
Chemokine
medicine.medical_specialty CIENCIAS MÉDICAS Y DE LA SALUD Time Factors Aortic Diseases VASCULAR CELL ADHESION MOLECULE-1 Inflammation Medicina Clínica Uridine Diphosphate Proinflammatory cytokine Cholesterol Dietary P2Y6 RECEPTOR Mice INFLAMMATION Internal medicine purl.org/becyt/ford/3.2 [https] medicine Animals Leukocyte Rolling URIDINE DIPHOSPHATE Aorta Bone Marrow Transplantation Mice Knockout biology Receptors Purinergic P2 Cell adhesion molecule Macrophages Purinergic receptor Transendothelial and Transepithelial Migration RECEPTORS PURINERGIC P2 Atherosclerosis Plaque Atherosclerotic Disease Models Animal CXCL2 Endocrinology ATHEROSCLEROSIS Receptors LDL CXCL5 Immunology biology.protein purl.org/becyt/ford/3 [https] Medicina Critica y de Emergencia Inflammation Mediators medicine.symptom Cardiology and Cardiovascular Medicine Signal Transduction Lipoprotein |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y 6 (P2Y 6 ) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y 6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y 6 in atherogenesis. Approach and Results— Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y 6 -deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor–deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y 6 than respective controls. Finally, P2Y 6 −/− /low-density lipoprotein receptor–deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y 6 +/+ /low-density lipoprotein receptor–deficient mice. Bone marrow transplantation identified a crucial role of P2Y 6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y 6 -deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y 6 -deficient macrophages took up less modified low-density lipoprotein cholesterol. Conclusions— We show for the first time that P2Y 6 deficiency limits atherosclerosis and plaque inflammation in mice. |
| Databáze: | OpenAIRE |
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