Liraglutide ameliorates myocardial damage in experimental diabetic rats by inhibiting pyroptosis via Sirt۱/AMPK signaling

Objective(s): Liraglutide, a well-established drug for treating diabetes mellitus (DM), has recently gained attention for its cardiovascular benefits in diabetes via multiple cellular activities; however, whether liraglutide improves myocardial damage by inhibiting pyroptosis and the mechanisms of these potential effects remain unknown.Materials and Methods: In this study, high-fat diet feeding and low-dose streptozotocin (STZ) injection were used to construct a rat DM model. Rats with fasting blood glucose (FBG) levels >۱۶.۷ mmol/l received subcutaneous injections of liraglutide (۰.۲ mg/kg) for ۴ weeks. Metabolic parameters, the heart weight/body weight (HW/BW) ratio, and histopathology were examined. Protein levels of inflammatory, pyroptosis, and NOD-like receptor protein ۳ (NLRP۳) inflammasome markers were assessed via Western blotting. In in vitro studies, a sirtuin ۱ (Sirt۱) inhibitor (EX ۵۲۷, ۲۰۰ nM) and an AMP-activated protein kinase (AMPK) inhibitor (compound C, ۲۰ µM) were used to inhibit Sirt۱ and AMPK pathways, respectively.Results: Liraglutide significantly attenuated cardiac hypertrophy, pathological changes, inflammation, pyroptosis, and NLRP۳ inflammasome activation, accompanied by increased Sirt۱ and AMPK activation. Consistent with the in vivo results, liraglutide attenuated high glucose (HG)-induced pyroptosis and NLRP۳ inflammasome activation along with enhanced Sirt۱ and AMPK activation. After blockade of Sirt۱ and AMPK signaling, the protective effect of liraglutide was restrained. Notably, EX ۵۲۷ abolished the stimulatory effect of liraglutide on Sirt۱ and AMPK signaling, whereas compound C blunted AMPK signaling without affecting Sirt۱ signaling. Conclusion: Liraglutide may protect against myocardial damage by activating the Sirt۱/AMPK signaling pathways to inhibit cellular pyroptosis in DM.

Keywords:

Cardiovascular Disease , Diabetes Mellitus , Inflammasomes , Rats , Sirtuin ۱