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Review
. 2021 Oct 22;17(15):4353-4364.
doi: 10.7150/ijbs.66537. eCollection 2021.

IL-1β in atherosclerotic vascular calcification: From bench to bedside

Jialing Shen  1 , Ming Zhao  2 , Chunxiang Zhang  3   4 , Xiaolei Sun  1   2   3   5   6   4   7   8
Affiliations
Review

IL-1β in atherosclerotic vascular calcification: From bench to bedside

Jialing Shen et al. Int J Biol Sci. .

Abstract

Atherosclerotic vascular calcification contributes to increased risk of death in patients with cardiovascular diseases. Assessing the type and severity of inflammation is crucial in the treatment of numerous cardiovascular conditions. IL-1β, a potent proinflammatory cytokine, plays diverse roles in the pathogenesis of atherosclerotic vascular calcification. Several large-scale, population cohort trials have shown that the incidence of cardiovascular events is clinically reduced by the administration of anti-IL-1β therapy. Anti-IL-1β therapy might reduce the incidence of cardiovascular events by affecting atherosclerotic vascular calcification, but the mechanism underlying this effect remains unclear. In this review, we summarize current knowledge on the role of IL-1β in atherosclerotic vascular calcification, and describe the latest results reported in clinical trials evaluating anti-IL-1β therapies for the treatment of cardiovascular diseases. This review will aid in improving current understanding of the pathophysiological roles of IL-1β and mechanisms underlying its activity.

Keywords: IL-1β; cardiovascular events; signaling pathways; vascular calcification.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Vascular calcification in cardiovascular vessels and valves. (A) and (B) show vascular calcification in a 74-year-old woman with a history of rheumatic heart disease and hyperuricemia. (A) Representative CT image of vascular calcification in the left anterior descending (LAD, yellow arrow) and left circumflex artery (LCX, blue arrow) of the left coronary artery (LCA). (B) Representative CT image of vascular calcification in the mitral valve. Images (C), (D), and (E) show vascular calcification in a 56-year-old man with a history of arteriosclerosis obliterans (ASO), severe chronic limb ischemia accompanied by intractable and infectious ulcers, and type 2 diabetes mellitus (T2DM). (C) Representative infrarenal CT angiography (CTA) image shows multiple vascular calcifications. (D) Severe vascular calcification in the infrarenal aorta. (E) Severe vascular calcification in the distal popliteal artery and branches with stenosis and occlusion.
Figure 2
Figure 2
Signaling pathways involved in IL-1β—mediated regulation of atherosclerotic vascular calcification. (A) IL-1β activates JNK pathway by downregulating BMPR2 expression and subsequent BMPR2-dependent inhibition of JNK, which promotes endothelial to mesenchymal transition (EndMT), leading to BMP-9-induced osteogenic differentiation. (B) IL-1β inhibits the mobilization and infiltration of mesodermal progenitor cells (MPCs), which can bi-directionally differentiate into osteoblasts (OBs) or osteoclasts (OCs). While in hypercholesterolemia IL-1β enhances the mobilization and infiltration of Sca-1+/PDGFRα+ cells, which are differentiated from MPCs and the progenitor cells of OBs. PPARγ promotes the differentiation of MPCs into OCs. (C) IL-1β stimulates tissue-nonspecific alkaline phosphatase (TNAP) expression and activity in both vascular smooth muscle cells (VSMCs) and mesenchymal stem cells followed by pyrophosphate (PPi) degradation. PPi is an effective endogenous inhibitor of Ca10(PO4)6(OH), which is a major component of the calcified aorta. This chain of events accelerates atherosclerotic vascular calcification.
Figure 3
Figure 3
Stimulators regulating IL-1β expression accelerate atherosclerotic vascular calcification. The NLRP3 inflammasome participates in the regulation of the progression of atherosclerotic vascular calcification via two signaling pathways described as follows. (A) The reduced Rac2 activity, caused by compromised guanine nucleotide exchange factors (GEFs), elevates the expression of Rac1, which promotes activation of NF-κB pathway and production of reactive oxygen species (ROS). These events lead to the NLRP3 inflammasome production. (B) Extracellular cholesterol crystals are taken up by macrophages and activate the NLRP3 inflammasome. NLRP3 inflammasome-activated caspase-1 cleaves pro-IL-1β and induces the secretion of IL-1β. (C) Deletion of the gene encoding low-density lipoprotein receptor (LDL-R) contributes to elevation in IL-1β expression and subsequent vascular calcification independent of hypercholesterolemia. This cascade may be modulated by the Wnt and β-catenin signaling pathways.
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