IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury

Intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases CA²⁺ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial Enzymes, infarct area, CA²⁺ level, NLRP3/Caspase-1, and Pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block CA²⁺ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced CA²⁺ overload, inflammation and Pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited CA²⁺ overload, alleviated cardiomyocyte inflammation, and Pyroptosis. The increase of intracellular CA²⁺ level caused H/R-induced cardiomyocyte Pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits CA²⁺ overload, thus alleviating Pyroptosis and MI/R injury.