NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM), a common consequence of longstanding diabetes mellitus, is initiated by death of cardiomyocyte. Hyperglycemia-induced reactive oxygen species (ROS) overproduction is a major contributor of the chronic low-grade inflammation that characterizes as the DCM. ROS may promote the activation of nucleotide-binding oligomerization domain like receptor (NLR) pyrin domain containing 3 (NLRP3) inflammasome, a novel regulator of inflammation and cell death, by nuclear factor-kB (NF-κB) and thioredoxin interacting/inhibiting protein (TXNIP). NLRP3 inflammasome regulates the death of cardiomyocyte and activation of fibroblast in DCM, which is involved in the structural and functional disorder of DCM. However, comprehensive understanding of molecular mechanisms linking NLRP3 inflammasome and disorder of cardiomyocyte and fibroblast in DCM is lacking. Here, we review the molecular mechanism(s) of NLRP3 inflammasome activation in response to hyperglycemia in DCM.

Keywords: NLRP3 inflammasome; diabetic cardiomyopathy; inflammation; pyroptosis; thioredoxin interacting/inhibiting protein.

Figure 1

NLRP3 inflammasome activation in DCM. Hyperglycemia-induced reactive oxygen species (ROS) leads to nuclear factor-kB (NF-κB) and TXNIP overexpression. NF-κB increases the expression of NLRP3, pro-IL-18, and pro-IL-1β. TXNIP modulates the biological structure of NLRP3 leading to NLRP3 inflammasome assembly and pro-caspase-1 (pro-casp-1) autocleavage. Active caspase-1 (Casp-1) promotes pro-IL-18 and pro-IL-1β maturation, which facilitate inflammatory reaction. On the other hand, active caspase-1 cleaves GSDMD within the linker between its N-terminal (blue) and C-terminal (magenta). The released GSDMD-N domain oligomerizes to generate membrane pores, which disrupts the osmotic potential and leads to cell swelling and eventual lysis.

Figure 2

Crosstalk between NLRP3 inflammasome and RISK/HIF-2α in myocardial I/R injury. The HFHF diet induced-hyperlipidemia and hyperglycemia promote overexpression of ROS and then triggers the assembly of NLRP3 inflamamsome. The activation of NLRP3 inflammasome increase the secretion of IL-1β and IL-18. The proinflammatory cytokines accelerate the oxidative stress of mitochondrial, which in turn promotes the activation of NlRP3 inflammasome. Hyperlipidemia and hyperglycemia inhibit the phosphorylation of Reperfusion Injury Salvage Kinases (RISK) pathway (including AKT, ERK, and GSK-3β), and negatively impacts hypoxia inducible factor-2α (HIF-2α), which can worsen the mitochondrial oxidative unbalance. The I/R challenge can suppress the phosphorylation of AKT and GSK-3β, and induce the expression of ROS and activation of NLRP3.