Diabetic Cardiomyopathy Uncovered: Transcriptomics, NLRP3, and Carvedilol Mechanisms.

Abstract

Background: This study investigates the impact of a high-sugar environment on H9C2 cardiomyocytes and explores the protective effects of carvedilol in the context of diabetic cardiomyopathy (Dia-CM). Transcriptomic analysis identified 21,655 differentially expressed genes associated with Dia-CM, demonstrating significant separation among samples. Methods: H9C2 cardiomyocytes were cultured in a high-sugar environment to simulate Dia-CM conditions. Cell viability, cytokine levels, and protein expression were assessed using CCK-8 assays, ELISA, and Western blot techniques. Intervention experiments with NLRP3, caspase-1, and ROS inhibitors were conducted to evaluate their protective effects. The therapeutic potential of carvedilol was assessed by examining its impact on cell viability, cytokine levels, and key biomarkers. An in-depth analysis of carvedilol's regulatory effects on ROS and key proteins in H9C2 cells was also conducted. Results: In vitro, a high-sugar environment significantly reduced H9C2 cell survival, increased ROS levels, activated inflammatory responses, and upregulated NLRP3, caspase-1, and GSDMD-N proteins. Inhibitors of NLRP3, caspase-1, and ROS ameliorated these effects. Carvedilol treatment improved cell activity, reduced inflammatory cytokine levels, suppressed ROS production, and downregulated NLRP3, pro-caspase-1, GSDMD-N, and p-NF-κB proteins. Moderate-dose carvedilol exhibited optimal intervention effects. Conclusions: A high-sugar environment induces cardiomyocyte damage through ROS production and NLRP3 inflammasome activation. Inhibitors of NLRP3, caspase-1, and ROS provide effective protection. Carvedilol significantly mitigates the detrimental effects of a high-sugar environment on H9C2 cardiomyocytes, potentially through inhibiting the NLRP3-ASC inflammasome and caspase-1/GSDMD-dependent signaling pathway-mediated pyroptosis. These findings offer insights into Dia-CM mechanisms and highlight carvedilol as a promising therapeutic intervention.