Inhibition of Caspase-1-dependent pyroptosis alleviates myocardial ischemia/reperfusion injury during cardiopulmonary bypass (CPB) in type 2 diabetic rats

**Cardiovascular complications represent a major challenge in type 2 diabetes mellitus (T2DM), driven by complex interactions between chronic hyperglycemia, insulin resistance, and disruptions in lipid metabolism. Myocardial ischemia/reperfusion (MI/R) injury during cardiopulmonary bypass (CPB) further heightens cardiac vulnerability. This study investigates the role of Caspase-1-dependent pyroptosis in global MI/R injury in T2DM rats undergoing CPB, shedding light on the mechanisms responsible for increased myocardial damage in T2DM.**

A rat model of T2DM was established, and Mean Arterial Pressure (MAP), heart rate (HR), and hematocrit (Hct) were compared between T2DM and normal rats. After reperfusion, myocardial cell morphology, infarct size, mitochondrial ROS, and caspase-1 levels were measured, along with NLRP3, pro-caspase-1, caspase-1 p10, and GSDMD expression. Plasma biomarkers, including CK-MB, cTnI, IL-1β, and IL-18, were also evaluated. The role of Caspase-1-dependent pyroptosis in MI/R injury during CPB was further explored using the caspase-1 inhibitor VX-765 and the ROS scavenger NAC.

**Key findings**: T2DM rats exhibited impaired glucose tolerance but maintained stable hemodynamics during CPB. However, they displayed increased susceptibility to MI/R injury, evident from significant lipid accumulation, disrupted myocardial fibers, and enhanced apoptosis. The activation of caspase-1-mediated pyroptosis, along with elevated reactive oxygen species (ROS) production, amplified tissue damage and inflammation. Treatment with Belnacasan VX-765 reduced myocardial injury by inhibiting caspase-1 activation and dampening the inflammatory response. Similarly, NAC treatment decreased oxidative stress, partially suppressing ROS-driven caspase-1 activation and lessening myocardial damage.

This study demonstrates that **Caspase-1-dependent pyroptosis plays a pivotal role in exacerbating myocardial injury and inflammation in T2DM rats undergoing CPB**. The findings highlight the contribution of oxidative stress-induced ROS to caspase-1 activation, suggesting that targeting these pathways may reduce global MI/R injury in T2DM.