Intermittent caloric restriction protects against diabetic heart inflammation via GSDMD-dependent sFRP2-ATF6-NF-κB pathway.

BACKGROUND

Calorie restriction holds the potential in alleviating metabolic disorders and inflammation. However, the effects of intermittent caloric restriction (ICR) on cardiometabolic diseases remain poorly understood. In this study, we aimed to assess the protective role of ICR in both prediabetic and diabetic heart injury.

METHODS

Prediabetic and diabetic models were established using a high-fat diet and high-fat diet/streptozotocin in mice, respectively. Following the induction of prediabetes mellitus and diabetes mellitus, ICR was implemented to evaluate its therapeutic effect. As alterations of gasdermin D (GSDMD) expression were monitored, we investigated the relationship between the cardioprotective effect of ICR and GSDMD using human heart samples, GSDMD knockout mice and adeno-associated virus 9(AAV9). Through RNA-sequencing, the underlying mechanism of GSDMD-mediated diabetes-associated cardiac inflammation was further elucidated.

RESULTS

Our study indicated that ICR prevented cardiac dysfunction by alleviating cardiac lipid overaccumulation in prediabetic mice. Conversely, the effect of ICR on lipid overaccumulation were limited in diabetic mice. Instead, the cardioprotective effect of ICR was mediated through the inhibition of GSDMD-mediated cardiomyocyte pyroptosis and inflammation response in diabetic mice. In human hearts, the expression level of GSDMD were positively correlated with diabetes-induced heart injuries. Furthermore, GSDMD deficiency mimicked the cardioprotective effects of ICR, while GSDMD overexpression in cardiomyocytes offset the cardioprotective effect of ICR in diabetic mice. Mechanistically, the upregulation of GSDMD activated secreted Frizzled-related protein 2 (sFRP2)/ATF6/NF-κB pathway, exacerbating cardiac inflammation in diabetic hearts. Moreover, the replenishment of recombinant sFRP2 offset the cardiac benefits of GSDMD deficiency in diabetic mice.

CONCLUSIONS

Our study demonstrated the prevention of prediabetic and diabetic heart injury by ICR were mediated by alleviating cardiac lipid overaccumulation and inflammation, respectively. Moreover, targeting GSDMD-dependent sFRP2/ATF6/ NF-κB pathway conferred the cardioprotective effects of ICR and could serve as a potential therapeutic strategy for diabetic heart failure.