Interactions between PCSK9 and NLRP3 inflammasome signaling in atherosclerosis

Abstract

Atherosclerosis is an early pathological basis of numerous cardiovascular events that result in death or disability. Recent studies have described PCSK9 as a novel target for the treatment of atherosclerosis; PCSK9 is capable of degrading LDLR on the surface of hepatocytes through the regulation of lipid metabolism, and it can function as a novel inflammatory modulator in atherosclerosis. Inflammasomes are important intracellular multiprotein complexes that promote the inflammatory response in atherosclerosis. Among inflammasomes, the NLRP3 inflammasome is particularly notable because of its important role in the development of atherosclerotic disease. After activation, NLRP3 forms a complex with ASC and pro-caspase-1, converting pro-caspase-1 into activated caspase-1, which may trigger the release of IL-1β and IL-18 and contribute to the inflammatory response. Several recent studies have indicated that there may be interactions between PCSK9 and the NLRP3 inflammasome, which may contribute to the inflammatory response that drives atherosclerosis development and progression. On the one hand, the NLRP3 inflammasome plays an important role via IL-1β in regulating PCSK9 secretion. On the other hand, PCSK9 regulates caspase-1-dependent pyroptosis by initiating mtDNA damage and activating NLRP3 inflammasome signaling. This paper reviews the mechanisms underlying PCSK9 and NLRP3 inflammasome activation in the context of atherosclerosis. Furthermore, we describe the current understanding of the specific molecular mechanism underlying the interactions between PCSK9 and NLRP3 inflammasome signaling as well as the drug repositioning events that influence vascular cells and exert beneficial antiatherosclerotic effects. This review may provide a new therapeutic direction for the effective prevention and treatment of atherosclerosis in the clinic.

Maternal Obesity Modulates Cord Blood Concentrations of Proprotein Convertase Subtilisin/Kexin-type 9 Levels

“…Epigenetic remodeling during early life could constitute a molecular mechanism through which intrauterine stimuli can have an impact on gene regulation and DNA damage and repair [ 41-44 ]. A recent study showed hypomethylation of the PCSK9 gene in placentas of diabetic pregnancies compared with controls [ 45 ], and DNA methylation alterations in blood cells of offspring born to obese mothers have also been previously demonstrated [ 6 ].…”

Novel Anti-Inflammatory Therapies in Coronary Artery Disease and Acute Coronary Syndromes

“…Cohort and prospective studies have shown that the concentration of NLRP3 inflammasome, IL-1β, and IL-18 is increased in the atheromas and monocytes of the peripheral blood of patients with CAD and especially those with acute coronary syndromes (ACS) when compared to the control groups [ 30 , 31 ]. Of interest, NLRP3 inflammasome and, as a result, IL-1β, are also partly modulating the secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-established therapeutic target in CAD [ 32 ].…”

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

“…In the same regard, potent blockers of Ang-II such as fimasartan and losartan have shown a beneficial impact in severe CAVS patients with hypertension (clinicaltrials.gov/NCT03666351). Moreover, the targeting of renin–angiotensin–angiotensinogen system (RAAS) inhibitor therapy may impede CAVS progression and reduce the mortality risk in CAVS patients [ 185 ]. Thus, large-scale trials are needed to dissect this further therapy in delaying the development of CAVS.…”