NLRP3 inflammasome in cardiovascular diseases: Pathophysiological and pharmacological implications

Abstract

Growing evidence points out the importance of nucleotide‐binding oligomerization domain leucine‐rich repeat and pyrin domain‐containing protein 3 (NLRP3) inflammasome in the pathogenesis of cardiovascular diseases (CVDs), including hypertension, myocardial infarct (MI), ischemia, cardiomyopathies (CMs), heart failure (HF), and atherosclerosis. In this regard, intensive research efforts both in humans and in animal models of CVDs are being focused on the characterization of the pathophysiological role of NLRP3 inflammasome signaling in CVDs. In addition, clinical and preclinical evidence is coming to light that the pharmacological blockade of NLRP3 pathways with drugs, including novel chemical entities as well as drugs currently employed in the clinical practice, biologics and phytochemicals, could represent a suitable therapeutic approach for prevention and management of CVDs. On these bases, the present review article provides a comprehensive overview of clinical and preclinical studies about the role of NLRP3 inflammasome in the pathophysiology of CVDs, including hypertension, MI, ischemic injury, CMs, HF and atherosclerosis. In addition, particular attention has been focused on current evidence on the effects of drugs, biologics, and phytochemicals, targeting different steps of inflammasome signaling, in CVDs.

Gut Metabolite Trimethylamine-N-Oxide in Atherosclerosis: From Mechanism to Therapy

“…Apart from Nlrp3 inflammasome, mitogen-activated protein kinases (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are involved in the pathogenesis of chronic inflammation ( 47 ). In particular, the Nlrp3 inflammasome is a cytosolic multiprotein complex expressed in immune/inflammatory cells as well as cardiovascular system cells, including endothelial cells, myofibroblasts/fibroblasts, and cardiomyocytes, which, through the processing and release of interleukin (IL)-1β and IL-18 and the induction of cell death processes (pyroptosis, apoptosis, and necroptosis), plays a key role in the maintenance of host homeostasis and in sustaining the pathophysiological events underlying CVDs ( 48 ). Conversely, TMAO can release inflammatory factors (caspase-1, IL-1 β) ( 49 ) in a dose-and time-dependent manner by activating the reactive oxygen species (ROS)–thioredoxin-interacting protein (TXNIP) –NLRP3 signaling pathway ( 50 ) and inhibiting sirtun3 (SIRT3) –superoxide dismutase2 (SOD2)–mitochondrial ROS signaling pathway ( 51 ), thereby causing endothelial cell injury and aggravating the formation and development of atherosclerosis.…”

Promoting athero-protective immunity by vaccination with low density lipoprotein-derived antigens

“…These molecular signatures of damage or danger interact with Toll-like receptors, which act as pattern-recognition receptors, leading to the activation of NLRP3 inflammasome, with the eventual release of inflammatory pro-atherogenic cytokines (IL-1β, IL-6 and IL-18) that characterize the acute innate immune response (Fig. 1) [19]. Activation of the NLRP3 inflammasome requires a priming signal that can be generated through exposure to oxLDL-induced TLR-4 dependent signaling leading to nuclear factor κ-B (NFκB)-mediated increased production of pro-IL-18 and pro-IL-1.…”

Regulation of the Immune Microenvironment by an NLRP3 Inhibitor Contributes to Attenuation of Acute Right Ventricular Failure in Rats with Pulmonary Arterial Hypertension

“…7 Many studies have highlighted the association of NLRP3 activation with hypertension and cardiovascular disease. [8][9][10] A recent study demonstrated that through the NLRP3 inflammasome pathway, low-dose lipopolysaccharide (LPS; 2 mg/kg) is sufficient to induce cardiac dysfunction in NLRP3-A350V /CreT mutant mice. 11 NLRP3 mediates IL-1β expression and release, but the mechanism by which NLRP3 participates in regulation of the myocardial immune microenvironment in the inflammatory state by mediating the interaction between cardiomyocytes and macrophages has not yet been reported, and whether the NLRP3 inflammasome pathway contributes to RVF and the underlying mechanisms are largely unknown.…”