Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement
Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement
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DOI：
10.1038/s41598-020-68637-4
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发表时间：
2020-08-06
影响因子：
4.6
通讯作者：
Duncker, Dirk J.
中科院分区：
文献类型：
--
作者：
Heinonen, Ilkka;Sorop, Oana;Duncker, Dirk J.
在过去的几十年里，糖尿病代谢紊乱（DMetD）的患病率急剧上升。尽管越来越多的证据表明DMetD与心功能障碍有关，但DMetD诱导的早期心肌改变仍然不完全清楚。在此，我们在临床相关的大型动物模型中研究了早期dmetd相关的心脏变化。通过注射链脲佐菌素和高脂肪、高糖饮食，在成年雄性哥廷根猪中建立DMetD，而对照组动物保持正常的猪饲料。5个月后，通过超声心动图和血流动力学测量评估左心室功能，然后进行全面的生化、分子和组织学分析。以高血糖、高胆固醇血症和高甘油三酯血症为证据，发展了稳健的DMetD。DMetD导致左室亚硝基氧化还原平衡改变，超氧化物产生增加-主要是由于内皮一氧化氮合酶（eNOS）解偶联-一氧化氮（NO）产生减少，心肌基因表达改变，特别是与葡萄糖和脂肪酸代谢相关的基因-以及线粒体功能障碍。这些异常伴有分离心肌细胞被动力增加，左室舒张功能受损，左室峰值解扭速度降低，E/ E′增加。然而，在DMetD的这个阶段，左室重量、体积、胶原含量和心肌细胞横截面积没有变化。综上所述，在临床相关的大型动物模型中，DMetD导致心肌氧化应激、eNOS解偶联和NO生成减少，同时代谢基因表达谱改变和线粒体功能障碍。这些分子改变与心肌细胞硬化和早期舒张功能障碍有关，然后发生任何结构性心脏重塑。治疗应针对改善这些早期dmetd诱导的心肌改变，以防止发展为明显的心力衰竭。
The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Gottingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitrosoredox balance, increased superoxide production-principally due to endothelial nitric oxide synthase (eNOS) uncoupling-reduced nitric oxide (NO) production, alterations in myocardial gene- expressionparticularly genes related to glucose and fatty acid metabolism- and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e'. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profile and mitochondrial dysfunction. These molecular alterations are associated with stiffening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetD-induced myocardial changes to prevent the development of overt cardiac failure.