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. 2021 Nov 5;8:760140. doi: 10.3389/fcvm.2021.760140

Figure 2.

Figure 2

Targets for gene therapy of atherosclerosis and involved mechanism. The figure predominantly demonstrates two primary mechanisms of atherosclerosis: (1) lipid metabolism; (2) immunoreaction and inflammation. Low turbulent flow, oscillatory shear stress, LDL, and ApoB in plasma induce endothelial dysfunction and activate the inflammatory response in endothelial cells. Then endothelial inflammation triggers the expression of leukocyte adhesion molecules such as E and P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) on endothelial cell surface. These molecules promote monocytes adhered to endothelial cells and infiltrated into subendothelial layer. Monocyte chemotactic protein-1 (MCP-1) also helps recruit circulating monocytes to migrate to intima. Thereafter, monocytes differentiate into macrophages and engulf the oxidative LDL. The excessive accumulation of oxLDL in macrophages leads to foam cell formation. When PPARγ-LXRα in macrophage is upregulated, the overexpressed ABCA1 and ABCG1 promote cholesterol efflux to HDL, which is helpful to inhibit foam cell formation and prevent plaque progression. However, in pathologic conditions, PPARγ-LXRα is down-regulated thereby promoting foam cell formation. Meanwhile, endothelial dysfunction leads to secretion of PDGF, TGF-β, IL-6, IL-8 initiating VSMC migration. Among two major subtypes of macrophage, M1 predominates in athersclerotic plaque and secrets inflammatory factors while M2 exerts anti-inflammatory effects and anti-atherogenic effects. Antigen-presenting cells present LDL and ApoB to T cells in lymph nodes to activate adaptive immune response. Lipid metabolism involved mechanism has been elucidated in the manuscript. Targets in existing gene therapy experiments investigating atherosclerosis are marked by gene therapy vectors. In summary, gene therapies inactivating/disrupting PCSK9, ApoC3, and ApoB and gene therapies activating/correcting LDLR, ApoA-I, and PPARγ-LXRα play a protective role in atherosclerosis.