Abstract
Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorder–associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1–mediated (HMGB1-mediated) myocardial inflammation, which contributes to cardiac dysfunction. After illustrating the dysregulated inflammatory pathways in human and murine hearts upon metabolic stress, we revealed an increase in calpain-1 alongside profound oxidative stress and inflammation in the failing myocardium. Mechanistically, in neonatal rat cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes, HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids. Consequently, HMGB1 promoted a proinflammatory response in macrophages. In contrast, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9–delivered inhibitor of calpain-1 or its pharmacological inhibitor attenuated ROS and HMGB1-induced inflammation in the myocardium and mitigated HF in both male and female mice fed with an ultra-processed diet. Collectively, we have demonstrated the effects of suppressing calpain-1 and oxidative stress on alleviating myocardial inflammation via blockage of HMGB1 and cardiac dysfunction. The results provide a promising therapeutic strategy for preventing or treating HF in metabolic disorders.
Authors
Claire Ross, Sanskruti Ravindra Gare, Nasser H.O. Alatawi, Oveena Fonseka, Xinyi Chen, Jiayan Zhang, Yihua Han, Andrea Ruiz-Velasco, Riham R.E. Abouleisa, Yingjuan Liu, Xiangjun Zhao, Han Xiao, Bernard D. Keavney, Gareth J. Howell, Tao Wang, Tamer M.A. Mohamed, Elizabeth J. Cartwright, Wei Liu
Figure 2
Oxidative stress is associated with increased cardiac HMGB1 and calpain-1 upon ultra-processed diet (UPD).
