American Journal of Pathology
American Journal of Pathology
5 years ago

Aggravated post-infarct heart failure in type 2 diabetes is associated with impaired mitophagy and exaggerated inflammasome activation

Type 2 diabetes mellitus (T2DM) is a major risk factor for heart disease. Mortality rates following myocardial infarction (MI) are significantly increased in T2DM patients due to dysfunctional left ventricle (LV). However, molecular pathways underlying accelerated post-MI heart failure (HF) in T2DM remain unclear. We investigated the underlying mechanisms by inducing MI in a well-established model of T2DM and control mice. Cardiac imaging revealed a significantly decreased global LV ejection fraction (EF) in parallel with increased mortality post-MI in T2DM mice compared to controls. Genome-wide mRNA sequencing, immunoblot, electron microscopy, together with immunofluorescence staining for LC3 and p62 indicated an impaired mitophagy in peri-infarct regions of LV in T2DM mice compared to controls. Furthermore, defective mitophagy was associated with an increased release of mitochondrial DNA, resulting in Aim2 and NLRC4 inflammasome and caspase-I hyperactivation in cardiomyocytes and cardiac macrophages in peri-infarct regions of LV in T2DM mice. Consistent with inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-18 secretion were increased in T2DM mice. Our results indicate that T2DM aggravates post-MI HF through defective mitophagy - associated exaggerated inflammasome activation, cell death and IL-18 secretion, suggesting that restoring mitophagy and inhibiting inflammasome activation may serve as novel targets for the prevention and treatment of HF in T2DM.

Publisher URL: www.sciencedirect.com/science

DOI: S0002944017303279

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