Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Turku PET Centre, University of Turku, Turku, Finland.
Sci Rep. 2020 Aug 6;10(1):13173. doi: 10.1038/s41598-020-68637-4.
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 Göttingen 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 nitroso-redox balance, increased superoxide production-principally due to endothelial nitric oxide synthase (eNOS) uncoupling-reduced nitric oxide (NO) production, alterations in myocardial gene-expression-particularly 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.
在过去的几十年中，糖尿病代谢紊乱（DMetD）的患病率急剧上升。虽然越来越多的证据表明 DMetD 与心脏功能障碍有关，但早期 DMetD 引起的心肌改变仍不完全清楚。在这里，我们在一个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。DMetD 通过链脲佐菌素注射和高脂肪、高糖饮食在成年雄性哥廷根小型猪中建立，而对照动物仍食用正常猪饲料。五个月后，通过超声心动图和血液动力学测量评估左心室（LV）功能，随后进行全面的生化、分子和组织学分析。通过高血糖、高胆固醇血症和高三酰甘油血症证实了稳健的 DMetD 发展。DMetD 导致 LV 硝基-氧化还原平衡改变，超氧化物产生增加-主要是由于内皮型一氧化氮合酶（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-和线粒体功能障碍。这些异常伴随着分离的心肌细胞被动力的增加，以及 LV 舒张功能受损，表现为 LV 峰值解旋速度降低和 E/e'增加。然而，在 DMetD 的这个阶段，LV 重量、体积、胶原含量和心肌细胞横截面积没有变化。总之，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 产生减少，以及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僵硬和早期舒张功能障碍有关，而不会发生任何结构性心脏重塑。治疗应该旨在改善这些早期 DMetD 引起的心肌变化，以防止明显的心力衰竭发展。
