Abstract 646: The Paradoxical Role of TREM-Like 1 in Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory process of the vessel wall driven by an inflammatory state caused by the involvement of different cell populations, including platelets. The receptor Triggering Receptor Expressed on Myeloid Cells (TREM)-like transcript (TLT)-1 is prepacked in platelet α-granules and brought to the surface upon activation. TLT-1 has both membrane-bound and soluble forms (sTLT-1) and the latter has been found to enhance platelet activation as well as platelet-endothelial cell interactions. TLT-1 null mice (treml1-/-) have reduced platelet aggregation, are significantly more susceptible to lipopolysaccharide challenge compared to their wild type counterparts, and accordingly, hemorrhage in response to an acute inflammatory challenge. These results suggest that TLT-1 is a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms and in light of this, we hypothesized that TLT-1 plays an important role in atherosclerosis progression. To address this, we generated apoE-/-/treml1-/- double knockout mice [DKO]. We found that DKO mice fed an atherogenic diet (HFD) showed significantly increased weight gain when compared to apoE-/-. Accordingly, DKO mice showed increased total cholesterol and triglycerides compared to controls. Surprisingly, assessment of lesion size revealed that DKO mice have significantly smaller lesions in the aortic sinus at four and 12 weeks after HFD compared to apoE-/-. At 20 weeks, lesion differences are no longer significant, but compositional analysis revealed that DKO atherosclerotic lesions are less vulnerable as seen by decreased lesion calcification and increased smooth muscle cell content. Furthermore, q-rtPCR analysis of atherosclerosis-related genes revealed that TLT-1 differentially affects genes related to lipid metabolism (apo AI and B) and vascular inflammation (thrombospondin 4, PAI-1 and VGFR-2). While our data suggests that the smaller lesion size may be explained by lower platelet reactivity, differences in cholesterol levels suggest altered lipid metabolism which is supported by our metabolomics studies (González, M. et.al). Taken together TLT-1 plays a dual role in the progression of atherosclerosis.