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

Abstract

A therosclerosis is a chronic inflammatory disease that is characterized by modifications in the vascular, metabolic, and immune systems. The accumulation of leukocytes within atherosclerotic lesions is a process regulated at various levels, including mobilization, recruitment, and endothelial adhesion of monocytes, followed by their migration into the intima and differentiation into macrophages.1,2 Two major monocyte subsets can be distinguished in the blood based on differential expression of the chemokine receptors CCR2 and CX 3 CR1. The inflammatory monocytes express high levels of CCR2 but low levels of CX 3 CR1, whereas the patrolling monocytes have low levels of CCR2 and high levels of CX 3 CR1.3,4 Inflammatory monocytes rapidly enter the atherosclerotic plaque where they give rise to macrophages. As macrophages accumulate in the atherosclerotic lesion, they incorporate lipids and become foam cells, eventually forming necrotic cores that fragilize the plaque. The inflammatory milieu attracts diverse immune cells but also promotes vascular smooth muscle cell (VSMC) infiltration from the media. Accumulation of VSMCs and collagen synthesis by these cells is associated with a reduced risk of rupture. 5Four-and-a-half LIM domain protein 2 (FHL2, SLIM3) is the best-studied member of the LIM-only subclass of the LIM protein superfamily. LIM proteins are defined by the presence of ≥1 LIM domains composed of a conserved cysteine-rich module that mediates protein-protein interactions. 6 Multiple roles have been ascribed to FHL2. FHL2 exerts its function as a transcriptional cofactor, interacting with a broad range of transcription factors, and modulating the transcription of many proteins such as the androgen receptor, cAMP response element-binding protein, integrins, β-catenin, presenilin-2, ERK-2 (extracellular signal-regulated kinase), AP-1, and sphingosine kinase-1. [7][8][9][10][11][12] It modulates cellular processes such as cell survival, proliferation, and signal transduction.13 FHL2© 2015 American Heart Association, Inc.

Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5

“…In both myeloid and vascular cells, FHL2 also plays an important role in atherosclerosis by promoting proinflammatory chemokine production, adhesion-molecule expression, and proinflammatory monocyte recruitment [ 13 ], and FHL2 deletion attenuates the formation of atherosclerotic lesions induced by a cholesterol-enriched diet [ 14 ]. Furthermore, FHL2 was originally identified in the heart, and the association of FHL2 mutations with human cardiac hypertrophy reinforce both its importance in the heart and its relevance to human cardiac disease [ 15 , 16 , 17 ].…”

Deletion of the FHL2 gene attenuates intima‐media thickening in a partially ligated carotid artery ligated mouse model

“…19 Absence of FHL2 reduced the atherosclerotic plaque formation by regulating the inflammatory process including macrophage and monocyte recruitment and anti-inflammatory cytokine secretion. 13 The activated VSMCs undergo migration, proliferation and apoptosis. 20 A previous study showed that FHL2 deficiency with complete artery ligation enhanced neointimal formation by ERK phosphorylation and cyclin D1 increase.…”

“…FHL2 modulates BMP‐mediated VSMC phenotypic switching . FHL2 regulates the inflammatory response by decreasing pro‐inflammatory monocyte recruitment and macrophage content . FHL2 plays a critical role in various physiological and pathological processes, including proliferation and migration .…”

Macrophages

“…FHL2 (four and a half LIM domain protein-2) is shown to interfere with this process, leading to selective recruitment of Ly6C hi monocytes, in part through altered expression of CX3CL1 on endothelial cells, and CX3CR1 on monocytes. 41 Part of this phenotype may be related to FHL2-mediated repression of NR4A1. 42 Abnormal migratory behavior of plaque macrophages may impact the resolution of inflammation.…”