Baylor Heart and Vascular Institute, Dallas, TX, USA.
Imperial College London, London, UK.
Nat Rev Cardiol. 2023 Jul;20(7):443-462. doi: 10.1038/s41569-022-00824-4. Epub 2023 Jan 6.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂通过对衰竭心脏的直接作用减少心力衰竭事件，而与肾小管功能变化无关。在衰竭的心脏中，营养物质向心肌细胞的转运增加，但营养物质的利用受损，导致 ATP 产生不足和有害的葡萄糖和脂质副产物在细胞质中积累。这些副产物触发细胞保护营养剥夺途径的下调，从而促进细胞应激并破坏细胞存活。SGLT2 抑制剂通过三种互补机制恢复细胞内稳态：它们可能直接与营养剥夺和营养过剩传感器结合，以促进其细胞保护作用；它们可以通过促进线粒体健康（通过增加自噬通量来介导）和可能通过缓解细胞质中铁离子的不足来增加 ATP 的合成；并且它们可以直接抑制葡萄糖转运蛋白 1，从而减少细胞质中有毒代谢副产物的积累，并促进长链脂肪酸的氧化。SGLT2 抑制剂介导的自噬通量增加也促进了有害葡萄糖和脂质副产物的清除以及功能失调线粒体的处理，从而通过线粒体生物发生实现线粒体的更新。本综述描述了营养物质运输和代谢以及营养剥夺和营养过剩信号之间的协调相互作用，以解释 SGLT2 抑制剂如何逆转心力衰竭中观察到的深刻的营养、代谢和细胞异常，从而使心肌恢复健康的分子和细胞表型。
