背景:西方饮食对育龄妇女肥胖和糖尿病的不利影响对其后代的心血管健康构成了重大威胁。鉴于谷胱甘肽代谢和谷胱甘肽相关的抗氧化防御系统通过清除ROS和维持氧化还原稳态在心血管疾病中的关键作用,进一步探索它们的具体影响对于开发由母体西方饮食引起的心肌病的治疗策略至关重要。
方法:我们在C57/B6小鼠中建立了一个产前母体Western饮食暴露模型,通过组织学分析和超声心动图研究心脏形态和功能。RNA测序和分析用于阐明母体西方饮食和N-乙酰半胱氨酸治疗对心肌病的影响的潜在机制。此外,ELISAs,透射电子显微镜,和流式细胞术用于评估祖细胞中的抗氧化防御系统和线粒体ROS水平。
结果:N-乙酰半胱氨酸显著减轻心肌细胞肥大,心肌间质纤维化,胶原蛋白I型积累,和由母体西方饮食引起的左心室重构,尤其是男性后代。此外,N-乙酰半胱氨酸逆转了母体西方饮食导致的后代心肌中凋亡的增加和β/α-MyHC比率的增加。RNA测序和GSEA揭示了N-乙酰半胱氨酸的有益作用与其调节氧化磷酸化途径的能力有关。此外,怀孕期间N-乙酰半胱氨酸治疗可以显着提高谷胱甘肽水平,增强谷胱甘肽过氧化物酶(GPx)活性,并减轻由母体西方饮食引起的线粒体ROS的积累。
结论:N-乙酰半胱氨酸通过促进谷胱甘肽合成和增强GPx活性来减轻由母体西方饮食引起的心肌病,从而清除线粒体ROS并调节氧化磷酸化途径。
BACKGROUND: The adverse effects of a Western diet on obesity and diabetes among reproductive-aged women pose a significant threat to the cardiovascular health of their offspring. Given the crucial role of glutathione metabolism and glutathione-related antioxidant defense systems in cardiovascular diseases through scavenging ROS and maintaining redox homeostasis, further exploration of their specific influence is imperative to develop therapeutic strategies for cardiomyopathy induced by a maternal Western diet.
METHODS: We developed a prenatal maternal Western diet exposure model in C57/B6 mice to investigate cardiac morphology and function through histological analysis and echocardiography. RNA sequencing and analysis were utilized to elucidate the mechanisms underlying the impact of a maternal Western diet and N-acetylcysteine treatment on cardiomyopathy. Additionally, ELISAs, transmission electron microscopy, and flow cytometry were employed to assess the antioxidant defense system and mitochondrial ROS levels in progenitor cardiomyocytes.
RESULTS: N-acetylcysteine significantly mitigated cardiomyocyte hypertrophy, myocardial interstitial fibrosis, collagen type I accumulation, and left ventricular remodeling induced by a maternal Western diet, particularly in male offspring. Furthermore, N-acetylcysteine reversed the increase in apoptosis and the increase in the β/α-MyHC ratio in the myocardium of offspring that results from a maternal Western diet. RNA sequencing and GSEA revealed that the beneficial effects of N-acetylcysteine were linked to its ability to modulate oxidative phosphorylation pathways. Additionally, N-acetylcysteine treatment during pregnancy can markedly elevate glutathione levels, augment glutathione peroxidase (GPx) activity, and mitigate the accumulation of mitochondrial ROS caused by a maternal Western diet.
CONCLUSIONS: N-acetylcysteine mitigated cardiomyopathy induced by a maternal Western diet by bolstering glutathione synthesis and enhancing GPx activity, thereby scavenging mitochondrial ROS and modulating oxidative phosphorylation pathways.