Oh Chang Myung, Cho Sungsoo, Jang Ji Yong, Kim Hyeongseok, Chun Sukyung, Choi Minkyung, Park Sangkyu, Ko Young Guk
Division of Endocrinology and Metabolism, CHA Bundang Medical Center, School of Medicine CHA University, Seongnam, Korea.
Division of Cardiovascular medicine, Department of Internal medicine, Dankook University Hospital, Dankook University School of Medicine, Cheonan, Korea.
Korean Circ J. 2019 Dec;49(12):1183-1195. doi: 10.4070/kcj.2019.0180. Epub 2019 Jul 31.
Recent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes.
Cardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects.
Mice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor.
SGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.
近期研究表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可降低糖尿病患者心力衰竭（HF）相关住院风险及死亡率。然而，SGLT2抑制剂在非糖尿病患者中是否具有心血管益处尚不清楚。我们旨在确定SGLT2抑制剂恩格列净（EMPA）在非糖尿病性HF中是否具有保护作用。
通过腹腔注射阿霉素（Dox）诱导C57BL/6J小鼠发生心肌病。将HF小鼠分为正常饮食组（NCD）或含0.03%EMPA的NCD饮食组。然后分析它们的表型，并进行体外实验以揭示EMPA作用的潜在机制。
喂食含EMPA的NCD的小鼠心脏功能改善，纤维化减轻。体外研究显示了类似结果。非特异性SGLT抑制剂根皮苷对H9C2细胞中的Dox毒性未显示出任何保护作用。SGLT2抑制剂可导致血酮水平升高。β-羟基丁酸（βOHB）是一种与SGLT2抑制剂相关的众所周知的酮体，在H9C2细胞和Dox处理的小鼠中对Dox显示出保护作用。这些结果表明，升高βOHB可能是SGLT2抑制剂发挥保护作用的一个令人信服的机制。
SGLT2抑制剂对Dox诱导的小鼠HF具有保护作用。这意味着即使在非糖尿病HF患者中，SGLT2抑制剂治疗也可能是一种良好的治疗策略。
