Key result
Type 1 diabetes induces an absolute ~27% drop in LVEF via NLRP3 inflammasome pyroptosis.
Why the study?
AGEs accumulate in the myocardium and mediate T1DM cardiomyopathy, but the full signaling cascades engaged by AGEs—specifically whether they induce myocardial injury via NLRP3 inflammasome activation—remained largely unresolved.
Does the AGEs/RAGE axis induce myocardial injury and cardiomyocyte pyroptosis via the ROS/NF-κB/NLRP3 inflammasome pathway in Type 1 diabetic cardiomyopathy?
Does the AGEs/RAGE axis induce myocardial injury and cardiomyocyte pyroptosis via the ROS/NF-κB/NLRP3 inflammasome pathway in Type 1 diabetic cardiomyopathy?
Absolute Event Rate: 48.13% vs 75.13%
p-value: p=<0.001
This preclinical study demonstrates that AGEs drive cardiomyocyte pyroptosis and cardiac dysfunction in type 1 diabetic cardiomyopathy via the RAGE/ROS/NF-κB/NLRP3 signaling axis, identifying potential molecular targets to attenuate diabetic myocardial injury.
Hypothesis-generating for AGEs/RAGE blockade in T1DM cardiomyopathy; leaves open clinical translation and requires human trials.
Background Type 1 diabetes mellitus (T1DM) cardiomyopathy is a severe complication that typically follows an insidious onset and then progresses rapidly to heart failure and premature death. AGEs accumulate in the myocardium under hyperglycemic conditions and have emerged as important mediators of this diabetic complication, although the full signaling cascades engaged by AGEs remain largely unresolved. In the present study, we therefore investigated whether AGEs induce myocardial injury in T1DM via NLRP3 inflammasome activation. Methods A T1DM mouse model was established using streptozotocin (STZ) injections, and an in vitro model was generated by treating primary neonatal mouse cardiomyocytes with AGEs. Cardiac performance and morphological changes were examined via echocardiography and histopathological staining. Expression and activation of the NLRP3 signaling cascade were evaluated by Western blotting, ELISA, and immunofluorescence. Pyroptotic cell death was assessed by SYTOX green staining, PI uptake, and lactate dehydrogenase (LDH) release assay. Correlations between whole‐blood RAGE gene expression and inflammatory cytokine levels (IL‐1 β and IL‐18) in T1DM patients, along with myocardial abundance of RAGE, NLRP3, and N‐GSDMD in the experimental mice, were analyzed as exploratory descriptive observations. Results STZ‐induced T1DM mice exhibited sustained hyperglycemia (fasting blood glucose ≥ 11.1 mmol/L) and impaired cardiac function. Myocardial tissue from T1DM animals showed marked engagement of the NLRP3 signaling cascade, as evidenced by elevated NLRP3, cleaved caspase‐1 P20, and N‐GSDMD, enhanced ASC speck formation, and increased serum IL‐1 β levels. In vitro, AGEs treatment directly triggered the NLRP3 pathway and drove cardiomyocyte pyroptosis. Mechanistically, AGEs binding to RAGE triggered a burst of intracellular ROS, which led to NF‐ κ B activation and subsequent NLRP3 activation. These effects were suppressed by either the RAGE inhibitor FPS‐ZM1 or the ROS scavenger N‐acetylcysteine (NAC). Furthermore, MCC950 treatment significantly attenuated AGE‐induced caspase‐1 activation, IL‐1 β /IL‐18 secretion, and N‐GSDMD expression, confirming that NLRP3 is a necessary mediator of this signaling cascade. SYTOX green staining, PI uptake, and LDH release assays further demonstrated that AGE‐induced pyroptotic cell death was blocked by FPS‐ZM1, NAC, and MCC950, indicating that pyroptosis occurs specifically through the RAGE/ROS/NLRP3 axis. Correlation analyses revealed that RAGE transcript levels in whole blood from T1DM patients positively correlated with circulating IL‐1 β and IL‐18. In the diabetic mouse heart, RAGE, NLRP3, and N‐GSDMD protein levels were analyzed as exploratory descriptive observations and showed a consistent pattern of coexpression at the individual level. Conclusion AGEs promote NLRP3 inflammasome activation in cardiomyocytes via the RAGE/ROS/NF‐ κ B signaling axis, driving inflammatory responses and pyroptosis, thereby contributing to the progression of T1DM cardiomyopathy. These observations imply that modulating this signaling axis could serve as a promising therapeutic strategy for treating T1DM cardiomyopathy.
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Li et al. (2026) studied Type 1 diabetic cardiomyopathy (n=12). Streptozotocin (STZ)-induced T1DM (in vivo) / AGEs with FPS-ZM1, NAC, or MCC950 (in vitro) vs. Control group / Vehicle was evaluated on Left ventricular ejection fraction (LVEF%) (p=<0.001). STZ-induced Type 1 diabetes reduced left ventricular ejection fraction in mice (48.13% vs 75.13%, p<0.001) and activated cardiomyocyte NLRP3 inflammasome pyroptosis via the AGEs/RAGE/ROS/NF-kB axis.
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