Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX. Imperial College, London, United Kingdom.
Circulation. 2020 Jun 23;141(25):2095-2105. doi: 10.1161/CIRCULATIONAHA.119.045561. Epub 2020 Mar 13.
Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by 2 intriguing features: ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia inducible factors (HIFs; especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeogenesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. HIFs act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. The activation of SIRT1, AMPK, and HIF-2α enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. It is interesting that type 2 diabetes mellitus, obesity, chronic heart failure, and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by downregulating SIRT1, AMPK, and HIF-2α, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK, and HIF-2α, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.
钠-葡萄糖共转运蛋白 2 抑制剂可降低严重心力衰竭和不良肾脏事件的风险，但尚不清楚其获益的机制。SGLT2 抑制剂的治疗有两个有趣的特点：酮体生成和红细胞增多。这两者都反映了诱导类似于禁食和缺氧的转录范例，该范例能够恢复和维持细胞内环境平衡和存活。在感知到营养和氧气缺乏时，细胞会激活低能量传感器，包括 Sirtuin-1（SIRT1）、AMP 激活的蛋白激酶（AMPK）和缺氧诱导因子（HIF；特别是 HIF-2α）；这些酶和转录因子是维持细胞内环境平衡的数百种基因和蛋白质的主要调节剂。SIRT1 的激活（通过促进糖异生和脂肪酸氧化的作用）驱动酮体生成，与 AMPK 协同作用，可直接抑制炎症小体激活并维持线粒体容量和稳定性。HIF 可促进氧气输送（通过刺激促红细胞生成素和红细胞生成）并减少氧气消耗。SIRT1、AMPK 和 HIF-2α 的激活增强了自噬，这是一种依赖溶酶体的降解途径，可清除危险成分，特别是受损的线粒体和过氧化物酶体，它们是氧化应激的主要来源，也是细胞功能障碍和死亡的触发因素。SIRT1 和 AMPK 还作用于钠转运机制以降低细胞内钠浓度。有趣的是，2 型糖尿病、肥胖症、慢性心力衰竭和慢性肾衰竭的特征是细胞内葡萄糖和脂质中间体的积累，这些中间体被细胞视为能量过剩的指标。细胞通过下调 SIRT1、AMPK 和 HIF-2α 作出反应，从而导致自噬流受损，并加速心肌病和肾病的发生。SGLT2 抑制剂通过触发类似禁食和缺氧的状态来逆转这种适应性不良的信号转导，包括 SIRT1、AMPK 和 HIF-2α 的激活、自噬流的增强、细胞应激的减少、细胞内钠流入的减少以及线粒体内环境平衡的恢复。该机制框架阐明了大型随机试验的结果以及酮体生成和红细胞增多与这些药物的心脏保护和肾脏保护益处之间的密切关联。
