Targeting the residual cardiovascular risk by specific anti-inflammatory interventions as a therapeutic strategy in atherosclerosis

• Published in: Pharmacological research 2022-04, Vol.178, p.106157-106157, Article 106157
• Main Authors: Hafiane, Anouar, Daskalopoulou, Stella S.
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; CANTOS; Cardiovascular disease; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - prevention & control; Heart Disease Risk Factors; Humans; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; NLRP3 Inflammasome; Residual cardiovascular risk; Risk Factors
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2022.106157

Chronic subclinical inflammation is a key process in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Along with lipids, inflammation is essential for the initiation and progression of atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine secretion. Several pro-inflammatory cytokines have been described in the primary and secondary prevention of ASCVD. Although extensive work over the past decades has established the role of lipid-lowering medications in the prevention and treatment of ASCVD, modulation of inflammation is a subject of active debate. It remains to be confirmed whether targeting the residual cardiovascular risk by adding anti-inflammatory agents to the conventional cardiovascular treatment becomes a shifting paradigm for ASCVD management. This review aims to discuss novel therapeutic agents targeting inflammatory pathways in ASCVD in light of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial results. Further we discuss the effects of different anti-inflammatory agents administered in patients with ASCVD and their potential to change clinical practice in preventive cardiology. Potential therapeutic targets for NLRP3 inflammasome blockage to interleukin-1 to interleukin-6 signaling pathway. Extracellular stimulus, crystalline structures (including cholesterol crystals), ATP and K+ efflux through the ATP-gated P2X7 channel can activate NLRP3 inflammasome. NLRP3 activation leads to active caspase-1, which cleaves the proforms of IL-1β and IL-18 into their mature forms. This result in production of pro-IL-1β to IL-1β with consequent downstream effects on IL-6. Several agents have been studied targeting different components of the NLRP3 inflammasome pathway. Potential interventions include canakinumab, anakinra, tocilizumab, methotrexate, and colchicine. MCC950 could inhibit ATPase activity of NLRP3 and inhibit NLRP3 oligomerization. Colchicine and MCC950 block NLRP3 inflammasome activation through disruption of ASC oligomerization. Colchicine could also halt lysosome damage and P2X7 receptor activity, and consequently, prevent NLRP3 inflammasome activation. Canakinumab block IL-1β. Statins, as substrates for organic anion transporting polypeptide (OATP) transporter, decrease cellular cholesterol production through inhibition of mevalonate conversion, which results in suppression of the TLR4/MyD88/NF-ĸB signaling pathway and a reduction in the form