Shannon M Jones1, Adrien Mann1, Kelsey Conrad1,2, Keith Saum1,3, David E Hall4,5, Lisa M McKinney1, Nathan Robbins1, Joel Thompson6, Abigail D Peairs4,5, Eric Camerer7, Katey J Rayner8, Michael Tranter1,2, Nigel Mackman9, A Phillip Owens10,2. 1. From the Division of Cardiovascular Health and Disease (S.M.J., A.M., K.C., K.S., L.M.M., N.R., M.T., A.P.O.). 2. Pathobiology and Molecular Medicine Program (K.C., M.T., A.P.O.). 3. University of Cincinnati Medical Scientist Training Program (K.S.). 4. Department of Nutritional Sciences, College of Allied Health (D.E.H., A.D.P.). 5. Department of Internal Medicine (D.E.H., A.D.P.), University of Cincinnati College of Medicine, OH. 6. Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky, Lexington (J.T.). 7. INSERM U970, Paris Cardiovascular Research Centre, France (E.C.). 8. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa Heart Institute, Ontario, Canada (K.J.R.). 9. Division of Hematology and Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill (N.M.). 10. From the Division of Cardiovascular Health and Disease (S.M.J., A.M., K.C., K.S., L.M.M., N.R., M.T., A.P.O.) phillip.owens@uc.edu.
Abstract
OBJECTIVE: PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS: PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient (Ldlr-/-) mice (8-12 weeks old) that were Par2+/+ or Par2-/- were fed a fat- and cholesterol-enriched diet for 12 or 24 weeks. PAR2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on nonhematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokines Ccl2 and Cxcl1 in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using isolated primary vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced Ccl2 and Cxcl1 mRNA expression and protein release into the supernatant resulting in less monocyte migration. CONCLUSIONS: Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting Ccl2- and Cxcl1-induced monocyte infiltration.
OBJECTIVE:PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS:PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient (Ldlr-/-)mice (8-12 weeks old) that were Par2+/+ or Par2-/- were fed a fat- and cholesterol-enriched diet for 12 or 24 weeks. PAR2deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on nonhematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokines Ccl2 and Cxcl1 in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using isolated primary vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced Ccl2 and Cxcl1 mRNA expression and protein release into the supernatant resulting in less monocyte migration. CONCLUSIONS: Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting Ccl2- and Cxcl1-induced monocyte infiltration.
Authors: Nina Wronkowitz; Sven W Görgens; Tania Romacho; Laura A Villalobos; Carlos F Sánchez-Ferrer; Concepción Peiró; Henrike Sell; Jürgen Eckel Journal: Biochim Biophys Acta Date: 2014-06-11
Authors: C Napoli; F de Nigris; J L Wallace; M D Hollenberg; G Tajana; G De Rosa; V Sica; G Cirino Journal: J Clin Pathol Date: 2004-05 Impact factor: 3.411
Authors: Morteza Naghavi; Peter Libby; Erling Falk; S Ward Casscells; Silvio Litovsky; John Rumberger; Juan Jose Badimon; Christodoulos Stefanadis; Pedro Moreno; Gerard Pasterkamp; Zahi Fayad; Peter H Stone; Sergio Waxman; Paolo Raggi; Mohammad Madjid; Alireza Zarrabi; Allen Burke; Chun Yuan; Peter J Fitzgerald; David S Siscovick; Chris L de Korte; Masanori Aikawa; K E Juhani Airaksinen; Gerd Assmann; Christoph R Becker; James H Chesebro; Andrew Farb; Zorina S Galis; Chris Jackson; Ik-Kyung Jang; Wolfgang Koenig; Robert A Lodder; Keith March; Jasenka Demirovic; Mohamad Navab; Silvia G Priori; Mark D Rekhter; Raymond Bahr; Scott M Grundy; Roxana Mehran; Antonio Colombo; Eric Boerwinkle; Christie Ballantyne; William Insull; Robert S Schwartz; Robert Vogel; Patrick W Serruys; Goran K Hansson; David P Faxon; Sanjay Kaul; Helmut Drexler; Philip Greenland; James E Muller; Renu Virmani; Paul M Ridker; Douglas P Zipes; Prediman K Shah; James T Willerson Journal: Circulation Date: 2003-10-07 Impact factor: 29.690
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2019-12-23 Impact factor: 8.311
Authors: Rajashree Rana; Andrew M Shearer; Elizabeth K Fletcher; Nga Nguyen; Srijoy Guha; Daniel H Cox; Manal Abdelmalek; Ying Wang; James D Baleja; Lidija Covic; Athan Kuliopulos Journal: Mol Metab Date: 2019-08-28 Impact factor: 7.422