Role of pyroptosis in diabetic cardiomyopathy: an updated review

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…

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.