Role of pyroptosis in cardiovascular disease

Abstract

Cardiac function is determined by the dynamic equilibrium of various cell types and the extracellular matrix that composes the heart. Cardiovascular diseases (CVDs), especially atherosclerosis and myocardial infarction, are often accompanied by cell death and acute/chronic inflammatory reactions. Caspase-dependent pyroptosis is characterized by the activation of pathways leading to the activation of NOD-like receptors, especially the NLRP3 inflammasome and its downstream effector inflammatory factors interleukin (IL)-1β and IL-18. Many studies in the past decade have investigated the role of pyroptosis in CVDs. The findings of these studies have led to the development of therapeutic approaches based on the regulation of pyroptosis, and some of these approaches are in clinical trials. This review summarizes the molecular mechanisms, regulation and cellular effects of pyroptosis briefly and then discusses the current pyroptosis studies in CVD research.

Keywords: atherosclerosis; cardiovascular disease; inflammation; pyroptosis.

Figure 1

Caspase‐1–dependent and independent pyroptotic pathway. In caspase‐1–dependent pyroptosis pathway, the cells activate their respective inflammasome (including NLRP3, AIM2 or pyrin) through the action of pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs), under the stimulation of hyperlipidaemia, hyperglycaemia and inflammation; NLRP3 oligomerizes and recruits ASC and pro–caspase‐1, triggering the activation of caspase‐1 and the maturation and secretion of pro‐inflammatory cytokines such as IL‐1β and IL‐18. GSDMD‐N formed by inflammatory caspase cleavage then mediates cell membrane pore formation, and promotes inflammatory factor release, cell swelling and pyroptosis. In caspase‐1–independent pyroptosis pathway, Gram‐negative bacterial cell wall component LPS activates caspase‐4/5/11 pathway to mediate cell pyroptosis

Figure 2

Multiple pathways that mediate pyroptosis. Various factors can activate the inflammasome to trigger pyroptosis. (1) Non‐pathogen stimulating factors such as hyperlipidaemia/hyperglycaemia activate the NLRP3 inflammasome through danger‐associated molecular patterns (DAMPs). NLRP3 interacts with ASC through an N‐terminal PYD domain, which then recruits pro–caspase‐1, promoting the maturation and release of IL‐1β and IL‐18. (2) Pathogen‐stimulated activation of PRRs, such TLR4, activates NF‐κB, leading to the transcription and translation of NLRP3 and then triggers pyroptosis. (3) The AIM2 inflammasome can directly bind double‐stranded DNA (dsDNA) via its HIN200 domain. Binding of dsDNA, leads to AIM2 oligomerization and the recruitment of the adaptor ASC via PYD‐PYD interactions. Once activated, the inflammasomes act as platforms to trigger caspase‐1 expression and the subsequent release of cytokines and pyroptosis. (4) Upon activation of the pyrin inflammasome, pyrin responds to disturbances in cytoplasmic homeostasis caused by infections, and the subsequent inactivation of the RhoA GTPase leads to pyrin activation, inflammasome assembly and pyroptotic cell death. (5) Oxidative stress‐induced phagocytosis of particles or live pathogens leads to lysosome rupture, releasing cathepsin B (CSTB), which facilitates the interaction between NLRP3 and ASC, thereby inducing pyroptosis. (6) The adipokine visfatin activates the NLRP3 inflammasome to trigger inflammasome activation directly or indirectly through an uncharacterized pathway, especially in obesity‐related diseases

Figure 3

Schematic of the main molecular pathways in pyroptosis in VECs and VSMCs in CVDs. Hyperlipidaemia/hyperglycaemia causes mitochondrial dysfunction (MDF)‐induced generation of reactive oxygen species (ROS), which leads to NF‐κB activation and thioredoxin‐interacting protein (TXNIP) overexpression. NF‐kB–activated NLRP3 inflammasome and maturation of IL‐18 and IL‐1β facilitate inflammatory reaction. Activated caspase‐1 cleaves GSDMD and forms the GSDMD‐N domain, which oligomerizes to generate membrane pores, which disrupt the osmotic potential and lead to cell swelling and eventual lysis

Figure 4

Schematic of the primary molecular pathways leading to pyroptosis in monocytes/macrophages in CVDs. Internalization of oxidized low‐density lipoprotein (oxLDL) by macrophages through CD36 receptor leads to intracellular gathering of cholesterol crystals in large phagolysosomal compartments. Cholesterol crystals can activate the NLRP3 inflammasome through lysosomal damage. oxLDL can also activate the NLRP3 inflammasome via the TLRs/NF‐κB pathway. Activated NLRP3 inflammasome induces the release of mature IL‐1β and IL‐18 and further leads to inflammatory cell infiltration and pyroptosis