Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE-/- Mice

Objective-Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial cells, vascular smooth muscle cells, and leukocytes. It regulates cell survival, migration, and inflammatory response, but its role in atherogenesis is unknown. Approach and Results-To investigate the role of FHL2 in atherosclerosis, FHL2-deficient mice were crossed with ApoE-deficient mice, to generate ApoE/FHL2(-/-) mice. After high-fat diet, ApoE/FHL2(-/-) mice had significantly smaller atherosclerotic plaques than ApoE(-/-) mice in the aortic sinus, the brachiocephalic artery, and the aorta. This was associated with enhanced collagen and smooth muscle cell contents and a 2-fold reduction in macrophage content within the plaques of ApoE/FHL-2(-/-) versus ApoE(-/-) mice. This could be explained, in part, by the reduction in aortic ICAM-1 (intracellular adhesion molecule) mRNA and VCAM-1 (vascular cell adhesion molecule) protein expression in the plaque. Aortic gene expression of the chemokines CX(3)CL1 and CCL5 was increased in ApoE/FHL2(-/-) versus ApoE(-/-) mice. Peritoneal thioglycollate injection elicited equivalent numbers of monocytes and macrophages in both groups, but a significantly lower number of proinflammatory Ly6C high monocytes were recruited in ApoE/FHL2(-/-) versus ApoE(-/-) mice. Furthermore, mRNA levels of CX(3)CR1 were 2-fold higher in monocytes from ApoE/FHL2(-/-) versus 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 diet, both chimeric groups developed smaller plaques than ApoE(-/-) transplanted with ApoE(-/-) bone marrow. Conclusions-These results suggest that FHL2 in both myeloid and vascular cells may play an important role in atherosclerosis by promoting proinflammatory chemokine production, adhesion molecule expression, and proinflammatory monocyte recruitment.