Translational research : the journal of laboratory and clinical medicine · 2025
Intermittent caloric restriction protects against diabetic heart inflammation via GSDMD-dependent sFRP2-ATF6-NF-κB pathway.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lin Kaibin, Zhai Changlin, Wang Ai, Lan Yang, Zhao Yun, Zhai Qiwei, Ge Junbo, Yan Yan
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsMiceHumansNF-kappa BPhosphate-Binding ProteinsSignal TransductionDiabetes Mellitus, ExperimentalInflammationMaleMembrane ProteinsCaloric RestrictionActivating Transcription Factor 6Mice, Inbred C57BLIntracellular Signaling Peptides and ProteinsMice, KnockoutDiabetic CardiomyopathiesDiet, High-FatGasderminsSecreted Frizzled-Related Proteins