The role of ERGIC-53 in the heart under diabetic stress

Background Diabetic stress is an important contributor to the onset and progression of heart failure (HF) by compromising both function and structure of the myocardium. Nonetheless, strategies for preventing and treating these prevalent outcomes are limited. The aetiology of HF in diabetes is multifactorial however, the exact molecular mechanisms underlying this phenomenon remain poorly understood. A reduction of endoplasmic reticulum-Golgi intermediate compartment 53 kDa protein (ERGIC-53) in failing hearts implies its involvement in the pathogenesis of cardiac dysfunction. Therefore, for the first time, we aim to investigate the role of ERGIC-53 in the heart under diabetic stress. Methods Diabetic stress was induced in mice using a 45% high-fat and high-sucrose diet (HFHSD) and intraperitoneally injected streptozotocin (STZ). Cardiomyocyte-specific ERGIC-53 deficient mice and adeno-associated virus 9 (AAV9) delivery system-mediated ERGIC-53 overexpressed mice were used for loss- and gain-of-function studies, respectively. Morphological assessments were carried out by histological analysis. Results Ergic-53-knockout mice displayed earlier, and more severe onset of diastolic dysfunction compared to control mice, as evidenced by prolonged isovolumic relaxation time (IVRT) and E/A ratio. Additionally, ERGIC-53 deficiency led to minor systolic dysfunction under stress, exhibited by decreased fractional shortening (FS%) and ejection fraction (EF%). ERGIC-53 loss triggered pathological cardiac remodelling, indicated by hypertrophic cardiomyocytes and increased fibrosis levels. Noticeably, enhanced levels of neutral lipids determined by oil red o staining was present in the Ergic-53 knockout myocardium. Consequently, significantly higher levels of reactive oxygen species (ROS) were observed in ERGIC-53-deficient hearts. On the other hand, genetic restoration of ERGIC-53 in the hearts of mice subjected to diabetic stress mitigated diastolic dysfunction, as evidenced by preserved IVRT and E/A ratio. Moreover, pathological cardiac remodelling was attenuated in ERGIC-53-overexpressed mice under diabetic stress, as indicated by significantly lower cardiac hypertrophy, fibrosis, lipid droplet accumulation and ROS generation. Conclusion In summary, our data provides useful insight into the cardioprotective role of ERGIC-53 under diabetic stress and highlights its therapeutic potential in preventing heart failure.