Abstract Body (Do not enter title and authors here): Diabetes worsens myocardial infarction (MI) pathologic progress, termed diabetic exacerbation of ischemic heart failure (IHF), with mechanisms and effective therapies remaining poorly understood. Circadian rhythm (CR) disruption is associated with heart failure, but its impact on diabetic IHF has not been studied. Adipocytes involve in maintaining physiological homeostasis and exhibit diurnal oscillations. However, the effects of circadian rhythm disruption on adipocyte dysfunction and diabetic IHF are unclear.
Adult C57BL6J mice and adipose tissue-specific BMAL1 (master circadian gene) knockout (ABK) adult C57BL6J mice were used as a diabetes model with a high-fat diet (HFD) fed for 12 weeks, and a normal diet (ND) as control. Myocardial ischemia-reperfusion (MI/R) injury was induced at Zeitgeber Time 12 (ZT12) in diabetic and ABK animals. Cardiac function assay revealed that, following MI/R, diabetic mice at ZT12 showed a significant worsening of cardiac ejection fraction (EF) (-5.2±2.2%), fractional shortening (FS), left ventricular radial strain (-4.5%±1.83), longitudinal strain, and radial (-1.31 ±0.54 1/s) and longitudinal strain rates. Mechanistically, the role of adipose circadian oscillation was investigated in ABK animals. Loss of BMAL1 in adipose tissue resulted in an increased cardiac injury, and further reduction of cardiac function in diabetic ABK animals on ZT12. Moreover, myocardial infarction was observed to be enlarged at ZT12 in the diabetic MI/R group compared to the ABK post-MI/R group, as indicated by TTC/Evans blue stain. This finding was further supported by TUNEL staining assays (cardiomyocyte apoptosis). Western blot analysis revealed an upregulation of apoptosis-related proteins, including cleaved caspase-3 and cleaved caspase-9, in the diabetic MI/R group at ZT12. Meanwhile, BMAL1 insufficiency (ABK) led to an increase in cleaved caspase-3 and cleaved caspase-9, with further augmentation observed in diabetic ABK animals post MI/R. Additionally, the amount of EVs was significantly increased at ZT12 in diabetic mice, whereas this phenomenon was not observed in ABK animals.
Our study suggests that disrupted circadian rhythms in adipose tissue promoted heart dysfunction and diabetic exacerbation of ischemic heart failure (IHF). Moreover, we propose that BMAL1 may alter adipose tissue EVs profiles to communicate with cardiomyocytes, with potential implications for improving therapeutic approaches for diabetes-related cardiomyopathy.