Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

Abstract

Chemerin and its receptor CMKLR1 (a G-protein-coupled receptor) are inducers of inflammation, and play an important role in diabetic cardiomyopathy (DCM). In this study, we investigated the role of the chemerin/CMKLR1 axis in mediating inflammation and cell death in DCM. Sprague-Dawley rats, treated with a high-fat diet and low-dose of streptozotocin, were used as a DCM model. CMKLR1 expression was knocked down by siRNA (CMKLR1-siRNA) to evaluate the role of CMKLR1 in DCM. Chemerintreated H9c2 cells were used to investigate the factors acting downstream of the chemerin/CMKLR1 axis. LDH release and EthD-III staining were used to measure the ratio of cell death in vitro. CMKLR1-siRNA and siRNA against nucleotide-binding oligomerization domain-like receptors 3 (NLRP3-siRNA) were used to explore the mechanism underlying chemerin-induced inflammation and cell death. The results showed that the expression of chemerin, CMKLR1, NLRP3, pro-caspase-1, activated caspase-1, and mature IL-1β was increased in the DCM model rat. Myocardium of DCM model rats exhibited fibrosis, hypertrophy, a disorganized ultrastructure, and impaired function. Pyroptosis was observed in vivo and in vitro. Silencing of CMKLR1 in vivo attenuated the expression of NLRP3 and activated caspase-1 and IL-1β. CMKLR1-siRNA treatment attenuated cardiac inflammation, fibrosis, hypertrophy, and pyroptosis, and improved cardiac function in vivo. Silencing of either CMKLR1 or NLRP3 suppressed the levels of activated caspase-1, IL-1β, and pyroptosis; however, silencing of both CMKLR1 and NLRP3 further decreased the levels of mature IL-1β and pyroptosis. Overall, the results showed that the chemerin/CMKLR1 axis contributed to the development of DCM and that the NLRP3 inflammasome mediated the chemerin/CMLR1-induced inflammation and pyroptosis. These data indicate that silencing of the CMKLR1 gene might exert a protective effect against DCM.

Decrease of chemerin by aerobic exercise improved glycolipid metabolism of diabetes through increasing key metabolism enzymes and protein mediated by PPARγ

“…In addition, studies have reported a close link between enhanced chemerin and IR (vital factor in the development of obesity), for example, excessive chemerin inhibited glucose intake and steatolysis of muscle tissue and lead to IR [45], and reducing the levels of serum chemerin in overweight, obese and type 2 diabetic patients would increase insulin sensitivity [46]. The vital role of chemerin/CMKLR1 in impairment of glycolipid metabolism including IR was demonstrated by chemerin or CMKLR1 knockout mice [47,48], and CMKLR1 gene silencing improved cardiac dysfunction in diabetic cardiomyopathy rats [49].…”

Role of Pyroptosis in Diabetes and Its Therapeutic Implications

“…A prior study also reported that NLRP3, caspase-1, and IL-1β mRNA expression levels were substantially upregulated in the DM group. 107 Fu et al have documented that lncRNA Kcnq1ot1 regulates pyroptosis in the diabetic heart tissues. 106 Western blotting, qRT-PCR, and immunofluorescence staining confirm that kcnq1ot1 and pyroptosis are initiated in HG-stimulated cardiac fibroblasts.…”

“…Increasing evidence reports that pyroptosis facilitates myocardial inflammation in DCM. 107 Wei et al have documented that hyperglycemia promotes cardiomyocyte pyroptosis via activating the AMPK-TXNIP signaling pathway in a high-fat diet-treated T2D mice model. 112 TXNIP overexpression leads to pyroptosis-mediated cardiomyocyte cell death.…”

“… 119 A recent study suggests that pyroptosis facilitates DCM progression via enhancing caspase-1 and NLRP3 inflammasome and IL-1β pro-inflammatory mediator release. 107 Kar et al have documented that pyroptosis-mediated cell death can trigger cardiac dysfunctions in high-fat diet-treated diabetic C57BL6 mice. 120 Therefore, these reports illustrate that pyroptosis plays a significant role in contributing to the pathogenesis of DCM.…”

“… 119 Xie et al have reported that the silencing of CMKLR1 in DCM rats attenuates the NLRP3 and caspase-1 and IL-1β protein expression levels. 107 The authors have demonstrated that the silencing of either CMKLR1 or NLRP3 can significantly suppress caspase-1 and IL-1β expression levels. These findings show that CMKLR1-gene silencing can have a protective effect against DCM.…”