Abstract 19071: Atherosclerosis is Reduced in Gremlin Haploinsufficient Apoe Knockout Mice

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Abstract

Introduction: In a previous study, we demonstrated that BMPs 2/4, as well as their antagonist Gremlin, were supra-regulated in aortas from animals prone to ATS fed with a high-fat diet (HFD). BMP signaling also modulates the migration of monocytes to the vascular wall, favoring local inflammation and consequent formation of atheroma plaques.

AIM: To study in vivo the immunomodulatory role of Gremlin in the development and progression of ATS.

Methods: We crossbred ApoE-/- and Grem +/- mice, creating a model of BMP gain-of-function, due to partial loss of the antagonist (Grem+/-ApoE-/- mice). These animals, as well as their controls, were fed with a HFD for 8 /16 weeks. Then, samples of blood and aortas were collected for evaluation of the inflammatory cell profile. Also, bone marrow cells were differentiated in vitro into DC and treated with recombinant BMP2/4 and/or Grem proteins.

Results: After 8 or 16 weeks of diet, LDL and total cholesterol blood levels were similar among Grem+/-ApoE-/- and ApoE-/- mice. Although, after 8 weeks of diet, total cell numbers found in Grem+/-ApoE-/- mouse aortas were half of those observed for ApoE-/- mice. We also noticed significantly lower numbers of monocytes (CD11b+) and DC (CD11b+CD11c+) in Grem+/-ApoE-/- mouse vessels. Withal, systemic blood counts of CD11b+CD11c+ cells were similar between the two groups, suggesting reduced migration to and/or proliferation, or increased death of those cells in aortas of Grem+/-ApoE-/- mice. In addition, we detected smaller aortic lesions in Grem+/-ApoE-/- mice after 16 weeks of HFD. We also investigated the influence of BMPs and/or Gremlin on bone marrow-derived DC. BMP signaling does not seem to have a direct effect on the activation state of those cells, as CD80, CD86 and MHCII surface expression levels were not altered following co-incubation of DC with BMPs or Gremlin.

Conclusion: Our results indicate that the loss of a Gremlin allele limits the development of ATS in ApoE-/- animals. Immune mechanisms seem to be involved, with lower presence of monocytes and DC in atherosclerotic plaques, without concomitant systemic changes in the levels of those cells. Additional studies are ongoing to better evaluate the contribution of BMPs and Gremlin for the fate of myeloid cells during atherogenesis.

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