Molecular mechanisms and genetic regulation in atherosclerosis

Abstract

Atherosclerosis (AS) manifested by lipid accumulation, extracellular matrix protein deposition, and calcification in the intima and media of the large to medium size arteries promoting arterial stiffness and reduction of elasticity. It has been accepted that AS leads to increased morbidity and mortality worldwide. Recent studies indicated that genetic abnormalities play an important role in the development of AS. Specific genetic mutation and histone modification have been found to induce AS formation. Furthermore, specific RNAs such as microRNAs and circular RNAs have been identified to play a crucial role in the progression of AS. Nevertheless, the mechanisms by which genetic mutation, DNA and histone modification, microRNAs and circular RNA induce AS still remain elusive. This review describes specific mechanisms and pathways through which genetic mutation, DNA and histone modification, microRNAs and circular RNA instigate AS. This review further provides a therapeutic strategic direction for the treatment of AS targeting genetic mechanisms.

Keywords: Atherosclerosis; CirRNA; Gene mutation; miRNAs.

Graphical abstract

Fig. 1

Diagrammatic illustration of molecular mechanism in genetic regulation of atherosclerosis. The mutation C to G base transversion in LDL gene (A1), G to A transversion in apoB and ABCA1 genes(A2) reduce lipid uptake which increase ox-LDL accumulation, inflammatory cytokine secretion inducing vascular inflammation and AS plaque formation. In addition, A to G and T to C transition in HNFA1 (A3) promote β cell dysfunction increasing plasma glucose inducing vascular inflammation and AS plaque development C: The continuous loss of modified histone such as H3K4me3, H3K9me2, and H3K27me3 promote the secretion of inflammatory cytokines production, inflammation and atherosclerosis. D: The activation miRNA-30c-5p, miRNA-155-5p bind to TNF-α and IL-1β,6 promoter regions to increase the inflammatory and atherosclerotic activity of TNF-α and IL-1β,6.

Fig. 2

A schematic illustration of signaling pathways involved in atherosclerosis: The altered levels of secreted cytokines including MCP-1, TNF-α, ox-LDL, AngII, IL-1β,6, INF-γ and ET-1 adhere to the respective membrane receptors. The interaction transduces signal to IKKB-NF-κB complex in the cytoplasm leading to the phosphorylation and degradation of I-κB to allow the nuclear translocation of NF-κB to activate the transcription of various cytokine which promote vascular inflammation and increase adhesion molecule expression to allow the binding of monocytes/macrophage leading to the formation of atherosclerosis. Moreover, miRNA-195, miRNA-30e-3p activate MAPK and Akt respectively to stimulate NF-κB vascular inflammatory activity and atherosclerosis. Furthermore, miRNA-155-5p, miRNA-126-5p, miRNA-146a/b,miRNA-146b-5p and miRNA-19b directly interact with NF-κB to promote vascular inflammation and atherosclerosis. However, MiRNA-30e-3p, MiRNA-455-3p, induce atherosclerosis by activating NF-κB via MAPK. Interestingly, MiRNA-127 prevent atherosclerosis by direct interaction and inhibition of NF-κB. In addition, the expression of CirANRIL upregulate p16^INK4a, p15^INK4b and p14^ARF, inhibit CDK, promote inflammation and atherosclerosis. Additionally, CirZNF609 upregulate miRNA 615 that inhibit the expression of MEFA2. MEFA2 inhibition accelerates endothelial cell dysfunction, inflammation, migration and microphage infiltration the occurrence of atherosclerosis.