Exacerbated post‐infarct pathological myocardial remodelling in diabetes is associated with impaired autophagy and aggravated NLRP3 inflammasome activation

BackgroundDiabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher mortality due tothe more frequent development of subsequent pathological myocardial remodelling and concomitant functional deteriora-tion. This study investigates the molecular pathways underlying accelerated cardiac remodelling in a well-established mousemodel of diabetes exposed to MI.Methods and resultsMyocardial infarction in DM mice was established by ligating the left anterior descending coronaryartery. Cardiac function was assessed by echocardiography. Myocardial hypertrophy and cardiacfibrosis were determinedhistologically 6 weeks post-MI or sham operation. Autophagy, the NLRP3 inflammasome, and caspase-1 were evaluatedby western blotting or immunofluorescence. Echocardiographic imaging revealed significantly increased left ventriculardilation in parallel with increased mortality after MI in DM mice (53.33%) compared with control mice (26.67%,P<0.05). Immunoblotting, electron microscopy, and immunofluorescence staining for LC3 and p62 indicated impaired au-tophagy in DM + MI mice compared with control mice (P<0.05). Furthermore, defective autophagy was associated withincreased NLRP3 inflammasome and caspase-1 hyperactivation in DM + MI mouse cardiomyocytes (P<0.05). Consistentwith NLRP3 inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-1βand IL-18 secretion were increasedin DM + MI mice (P<0.05). Importantly, the autophagy inducer and the NLRP3 inhibitor attenuated the cardiac remodellingof DM mice after MI.ConclusionIn summary, our results indicate that DM aggravates cardiac remodelling after MI through defective autophagyand associated exaggerated NLRP3 inflammasome activation, proinflammatory cytokine secretion, suggesting that restoringautophagy and inhibiting NLRP3 inflammasome activation may serve as novel targets for the prevention and treatment ofpost-infarct remodelling in DM.