Role of pyroptosis in diabetic cardiomyopathy: an updated review

Abstract

Diabetic cardiomyopathy (DCM), one of the common complications of diabetes, presents as a specific cardiomyopathy with anomalies in the structure and function of the heart. With the increasing prevalence of diabetes, DCM has a high morbidity and mortality worldwide. Recent studies have found that pyroptosis, as a programmed cell death accompanied by an inflammatory response, exacerbates the growth and genesis of DCM. These studies provide a theoretical basis for exploring the potential treatment of DCM. Therefore, this review aims to summarise the possible mechanisms by which pyroptosis promotes the development of DCM as well as the relevant studies targeting pyroptosis for the possible treatment of DCM, focusing on the molecular mechanisms of NLRP3 inflammasome-mediated pyroptosis, different cellular pyroptosis pathways associated with DCM, the effects of pyroptosis occurring in different cells on DCM, and the relevant drugs targeting NLRP3 inflammasome/pyroptosis for the treatment of DCM. This review might provide a fresh perspective and foundation for the development of therapeutic agents for DCM.

Keywords: NLRP3 inflammasome; diabetic cardiomyopathy; inflammation; mechanism; pyroptosis.

Figure 1

Brief molecular mechanism of Pyroptosis. (A) (canonical pathway): In the canonical pathway, when the host cell receptor recognizes various stimuli, it mainly includes pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), which can promote the activation of downstream pro-Caspase-1 into mature Csapase-1, and promote the assembly of inflammasome. Mature Caspase-1 can cleave GSDMD to form N-GASDMD. Subsequently, the N-terminal poreforming domain of GSDMD can non-selectively penetrate the cell membrane to form membrane pores, which further leads to cell swelling, cracking, and death. (B) (Non-canonical pathway): In the non-canonical pathway, LPS can directly bind to the CARD domain of Caspase-4 / 5 / 11 to achieve activation. The activated Caspase-4 / 5 / 11 can also cleave GSDMD to form N-GSDMD, thus promoting the occurrence of pyroptosis. (C) (Caspase-3-mediated pathway): Unlike the canonical and non-canonical pathways, activated Caspase-3 mainly mediates the formation of membrane pores by cutting GSDME and promoting the N-GSDME domain to the cell membrane, leading to the occurrence of pyroptosis. (D) (Caspase-8-mediated pathway): Under the stimulation of TNF-α, Caspase-8 can also specifically cleave GSDMC to produce N-GSDMC to induce pyroptosis.

Figure 2

Pyroptosis pathway associated with DCM. There are many pathways involved in the process of pyroptosis promoting the occurrence and development of DCM. In the NF-κB / NLRP3 signaling pathway, the TLR4 receptor senses various stimulating factors, separates the NF-κB in the cytoplasm from the inhibitory protein IκB, and transfers to the nucleus, resulting in an increase in the expression of NLRP3 and the activation of NLRP3 inflammasome. A high glucose environment can induce the production of a large number of ROS. TXNIP is a ROS-dependent NLRP3 inflammasome activation regulator. A large amount of ROS can promote the binding of TXNIP to NLRP3 and trigger the activation of NLRP3 inflammasome. As a transcription factor, Nrf2 can regulate cardiac homeostasis by controlling various antioxidant genes to inhibit oxidative stress. Nrf2 is transferred to the nucleus under the action of ROS and oxidative stress and binds to the promoter region of the antioxidant response element (ARE) to promote the production of antioxidant enzymes and protect cardiomyocytes. At the same time, Nrf2 can also inhibit NF-κB to reduce the formation of NLRP3 inflammasome and inhibit pyroptosis.

Figure 3

Pyroptosis in different cells promotes the development of DCM. The prolonged hyperglycemia causes pyroptosis of non-myocardial cells such as cardiomyocytes and macrophages, vascular endothelial cells, and cardiac fibroblasts, promoting poor cardiac remodeling and accelerating the development of DCM.