Group X Secreted Phospholipase A2 Limits the Development of Atherosclerosis in LDL Receptor–Null Mice

• DOI: 10.1161/atvbaha.112.300309
• Publication Date: 2013-01-25T05:16:43Z
• Authors: Hafid Ait-Oufella; Olivier Herbin; Charlotte Lahoute; Christelle Coatrieux; Xavier Loyer; Jeremie Joffre; Ludivine Laurans; Bhama Ramkhelawon; Olivier Blanc-Brude; Sonia Karabina; Christophe A. Girard; Christine Payré; Kei Yamamoto; Christoph J. Binder; Makoto Murakami; Alain Tedgui; Gérard Lambeau; Ziad Mallat
• Keywords: Male; Aortic Diseases; Aorta, Thoracic; Apoptosis; Mice, Transgenic; Adaptive Immunity; Mice; Necrosis; 03 medical and health sciences; 0302 clinical medicine; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; Animals; Group X Phospholipases A2; Humans; Cells, Cultured; Bone Marrow Transplantation; Mice, Knockout; Macrophages; Atherosclerosis; Coculture Techniques; Plaque, Atherosclerotic; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal

Objective— Several secreted phospholipases A2 (sPLA2s), including group IIA, III, V, and X, have been linked to the development of atherosclerosis, which led clinical testing A-002 (varespladib), a broad sPLA2 inhibitor for treatment coronary artery disease. Group X (PLA2G10) has most potent hydrolyzing activity toward phosphatidylcholine is believed play proatherogenic role. Methods Results— Here, we show that Ldlr –/– mice reconstituted with bone marrow from mouse X–deficient ( Pla2g10 ) unexpectedly display doubling plaque size compared +/+ chimeric mice. Macrophages are more susceptible apoptosis in vitro, associated 4-fold increase necrotic core vivo. In addition, exaggerated T lymphocyte (Th)1 immune response, enhanced T-cell infiltration atherosclerotic plaques. Interestingly, overexpression human PLA2G10 murine cells leads significant reduction Th1 response 50% lesion size. Conclusion— expression controls limits atherosclerosis. The results may provide an explanation recently reported inefficacy (varespladib) treat patients Indeed, nonselective inhibits both (groups IIA V) antiatherogenic (group X) sPLA2s. Our suggest selective targeting individual enzymes be better strategy cardiovascular diseases.