Atherosclerosis: A Comprehensive Review of Molecular Factors and Mechanisms

Abstract

Atherosclerosis, a condition characterized by the accumulation of lipids and a culprit behind cardiovascular events, has long been studied. However, in recent years, there has been an increase in interest in its initiation, with researchers shifting focus from traditional pathways involving the vascular infiltration of oxidized lipids and towards the novel presence of chronic inflammatory pathways. The accumulation of pro-inflammatory cytokines, in combination with the activation of transcription factors, creates a positive feedback loop that drives the creation and progression of atherosclerosis. From the upregulation of the nod-like receptor protein 3 (NLRP3) inflammasome and the Notch and Wnt pathways to the increased expression of VEGF-A and the downregulation of connexins Cx32, Cx37, and Cx40, these processes contribute further to endothelial dysfunction and plaque formation. Herein, we aim to provide insight into the molecular pathways and mechanisms implicated in the initiation and progression of atherosclerotic plaques, and to review the risk factors associated with their development.

Keywords: atherosclerosis; cardiovascular health; inflammation.

Figure 1

Figure showing the creation of the NLRP3 inflammasome and pro-inflammatory cytokines IL-1β and IL-18. The attachment of oxLDL on the CD36–TLR4–TLR6 signaling complex activates NF-κB, which translocates to the nucleus and binds to NF-κB-dependent promoters for the activation of target genes. The produced NLRP3 binds with an apoptosis-associated speck-like protein (ASC) and procaspase-1 to create an NLRP3 inflammasome. The NLRP3 inflammasome cleaves pro-caspase-1 into its active form caspase-1, which in turn cleaves pro-IL-1β and pro-IL-18 to their active isomers IL-1β and IL-18, respectively. It is important to note that the created IL-1β can bind to IL-1R on the extracellular surface of macrophages to further induce the formation of more IL-1β and IL-18, thus creating a pro-inflammatory environment [27].

Figure 2

Figure summarizing the pathophysiology of atherosclerosis. From the infiltration of LDLs to the creation of a calcified fibrous cap and its rupture, multiple factors contribute to the initiation and progression of atherosclerosis.

Figure 3

Intracellular portion of the Notch pathway. Once the intracellular domain of the Notch receptor (NICD) has been cleaved by the enzyme γ-secretase, it translocates to the nucleus to bind to transcription factors such as Mastermind-like proteins (MAMLs) and CSL for the activation of target transcription genes [62].

Figure 4

Summary of the inflammatory feedback mechanism in the initiation of atherosclerosis. Atherosclerosis is not just a collection of individual events but a positive feedback loop in which each step upregulates the previous one. The infiltration of LDLs into the tunica intima and the creation of lipid-rich macrophages in conjunction with inflammatory cytokines stimulate the progression of atherosclerosis.