Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Diabetes Obes Metab. 2022 Nov;24(11):2263-2272. doi: 10.1111/dom.14814. Epub 2022 Aug 1.
To investigate cardiac signalling pathways connecting substrate utilization with left ventricular remodelling in a murine pressure overload model.
Cardiac hypertrophy was induced by transverse aortic constriction surgery in 20-week-old C57BL/6J mice treated with or without the sodium-glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin (225 mg kg chow diet) for 10 weeks.
Ertugliflozin improved left ventricular function and reduced myocardial fibrosis. This occurred simultaneously with a fasting-like response characterized by improved glucose tolerance and increased ketone body concentrations. While cardiac insulin signalling was reduced in response to SGLT2 inhibition, AMP-activated protein kinase (AMPK) signalling was increased with induction of the fatty acid transporter cluster of differentiation 36 and phosphorylation of acetyl-CoA carboxylase (ACC). Further, enzymes responsible for ketone body catabolism (β-hydroxybutyrate dehydrogenase, succinyl-CoA:3-oxoacid-CoA transferase and acetyl-CoA acetyltransferase 1) were induced by SGLT2 inhibition. Ertugliflozin led to more cardiac abundance of fatty acids, tricarboxylic acid cycle metabolites and ATP. Downstream mechanistic target of rapamycin (mTOR) pathway, relevant for protein synthesis, cardiac hypertrophy and adverse cardiac remodelling, was reduced by SGLT2 inhibition, with alleviation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) providing a potential mechanism for abundant reduced left ventricular apoptosis and fibrosis.
SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin and increased AMPK signalling as a potential mechanism for less cardiac mTOR activation with alleviation of downstream ER stress, UPR and apoptosis.
在小鼠压力超负荷模型中，研究连接底物利用与左心室重构的心脏信号通路。
在 20 周龄 C57BL/6J 小鼠中通过横主动脉缩窄手术诱导心肌肥厚，并给予或不给予钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂恩格列净（225mg/kg 饲料饮食）治疗 10 周。
恩格列净改善了左心室功能并减少了心肌纤维化。这与禁食样反应同时发生，表现为葡萄糖耐量改善和酮体浓度增加。虽然 SGLT2 抑制导致心脏胰岛素信号降低，但 AMP 激活蛋白激酶（AMPK）信号增加，同时诱导脂肪酸转运蛋白簇分化 36 和乙酰辅酶 A 羧化酶（ACC）磷酸化。此外，酮体分解代谢的酶（β-羟丁酸脱氢酶、琥珀酰辅酶 A：3-氧代酸辅酶 A 转移酶和乙酰辅酶 A 乙酰转移酶 1）也被 SGLT2 抑制诱导。恩格列净导致心脏中脂肪酸、三羧酸循环代谢物和 ATP 的含量增加。下游雷帕霉素（mTOR）通路的机械靶标，与蛋白质合成、心肌肥厚和不良心脏重构有关，通过 SGLT2 抑制而减少，内质网（ER）应激和未折叠蛋白反应（UPR）的缓解为大量减少的左心室细胞凋亡和纤维化提供了潜在的机制。
SGLT2 抑制减少了心肌肥厚小鼠模型中的左心室纤维化。从机制上讲，这与心脏胰岛素减少和 AMPK 信号增加有关，这可能是心脏 mTOR 激活减少的潜在机制，同时缓解下游 ER 应激、UPR 和细胞凋亡。
