Effects of Sodium-Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice.
Effects of Sodium-Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice.
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DOI：
10.1161/jaha.120.019995
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发表时间：
2021-07-06
影响因子：
5.4
通讯作者：
Colucci WS
中科院分区：
文献类型：
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作者：
Croteau D;Luptak I;Chambers JM;Hobai I;Panagia M;Pimentel DR;Siwik DA;Qin F;Colucci WS
钠-葡萄糖连接转运蛋白 2 抑制剂可改善患有或不患有 2 型糖尿病的患者的心血管结局，但对心脏能量和线粒体功能的影响尚不清楚。我们评估了钠-葡萄糖连接转运蛋白 2 抑制对患有和不患有饮食诱发的糖尿病心肌病的小鼠心脏中线粒体功能、高能磷酸盐和编码线粒体蛋白的基因的影响。喂食对照饮食或高脂肪、高糖饮食的小鼠接受与饮食混合的艾格列净（0.5 毫克/克饮食），为期 4 个月。评估分离的线粒体的功能能力。通过 31P 核磁共振波谱评估高能磷酸盐，同时评估离体跳动心脏的收缩性能。高脂肪、高糖饮食导致心肌肥厚、舒张功能障碍、线粒体功能障碍和能量反应受损，而所有这些都被艾格列净预防。在这两种饮食中，艾格列净都会导致收缩储备超正常化，这是通过高工作需求时的速率×压力乘积来衡量的。同样，艾格列净最富集的心肌基因集是氧化磷酸化和脂肪酸代谢，这两者的富集均与饮食无关。厄图格列净不仅可以预防高脂肪、高蔗糖诱导的病理性心脏重塑，还可以改善收缩储备并诱导氧化磷酸化和脂肪酸代谢基因组的表达，而与糖尿病状态无关。钠-葡萄糖连接转运蛋白 2 抑制对心脏能量学和代谢的这些影响可能有助于改善与线粒体功能障碍相关的心脏病（例如心力衰竭）的结构和功能。
Inhibitors of the sodium‐glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium‐glucose linked transporter 2 inhibition on mitochondrial function, high‐energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet‐induced diabetic cardiomyopathy. Mice fed a control diet or a high‐fat, high‐sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High‐energy phosphates were assessed by 31P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high‐fat, high‐sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet. Ertugliflozin not only prevented high‐fat, high‐sucrose–induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium‐glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.