Abstract 12315: Four-and-a-Half LIM Domain Protein-2 Absence Reduces Atherogenesis in Apolipoprotein E-deficient Mice: Role of Monocytic Immune Cells

Abstract

Background: Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial and vascular smooth muscle cells. It negatively regulates endothelial cell survival and migration, but its role in atherogenesis is unknown. Methods and Results: FHL2-deficient (FHL2-/-) mice were crossed with apolipoprotein E-deficient (ApoE-/-) mice to generate ApoE/FHL2-/- mice. After high-fat, high-cholesterol diet, ApoE/FHL2-/- mice displayed significantly smaller atherosclerotic plaques than ApoE-/- mice in the aortic sinus, the brachiocephalic artery and the aorta. This was associated with significantly enhanced collagen and smooth muscle cell contents and a significant 2-fold reduction of macrophage content within the plaques of ApoE/FHL-2-/- vs ApoE-/- mice. There was a significant reduction in aortic ICAM-1 mRNA and VCAM-1 protein expression in the plaques of ApoE/FHL2-/- mice. Aortic gene expression of CX3CL1 and CCL5 was significantly increased in ApoE/FHL2-/- vs ApoE-/- mice. Peritoneal thioglycollate injection elicited equivalent numbers of monocytes and macrophages in both groups, but a significantly lower number of pro-inflammatory Ly6C-high monocytes were recruited in ApoE/FHL2-/- vs ApoE-/- mice. Furthermore, mRNA levels of CX3CR1 were 2-fold higher in monocytes from ApoE/FHL2-/- vs ApoE-/- mice. Finally, we investigated the potential importance of myeloid cell FHL2 deficiency in atherosclerosis. After being irradiated, ApoE-/- or ApoE/FHL2-/- mice were transplanted with ApoE-/- or ApoE/FHL2-/- bone marrow. After high-fat, high-cholesterol diet, both chimeric groups developed significantly smaller plaques than ApoE-/- mice transplanted with ApoE-/- bone marrow. Conclusion: These results suggest that FHL2 in both myeloid and vascular cells may play an important role in atherogenesis by promoting pro-inflammatory chemokine production, adhesion molecule expression, and pro-inflammatory monocyte recruitment.