Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, Turku 20520, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku 20520, Finland.
Biomed Pharmacother. 2024 Nov;180:117453. doi: 10.1016/j.biopha.2024.117453. Epub 2024 Sep 26.
Today, sodium glucose co-transporter 2 (SGLT2) inhibitors are more than diabetes drugs. They are also indicated in chronic heart failure (HF) treatment in both diabetic and non-diabetic patients, independently of the ejection fraction. Multiple mechanisms have been suggested behind the cardioprotective effects of SGLT2 inhibitors. However, the underlying mechanisms still remain largely unexplored. Here, we used a zebrafish embryo model to search for new potential players whereby SGLT2 inhibitors attenuate HF.
HF in zebrafish embryos was caused exposing them to chemically induced hypoxia. As a SGLT2 inhibitor, we used empagliflozin. Its effect on hypoxia-induced HF of the embryos was evaluated using video microscopy and calculation of fractional shortening (FS) of embryos´ hearts. RT-qPCR of brain natriuretic peptide (bnp) expression was also used to examine empagliflozin´s effect on HF. Transcriptome analysis of total RNA of the embryos was performed to search for new potential mechanisms contributing to the beneficial effect of empagliflozin on HF.
Empagliflozin significantly attenuated hypoxia-induced HF of zebrafish embryos as shown with improved FS of the hearts and decreased bnp expression. Transcriptome analysis revealed that the improvement of HF in response to empagliflozin was accompanied with decreased matrix metalloproteinase 13a (mmp13a) expression. Treatment of hypoxia-induced embryos with MMP13 inhibitor ameliorated the impaired heart function accordingly to the effect of empagliflozin. MMP13 inhibitor was not toxic to the embryos.
Our study shows that empagliflozin´s favorable effect on attenuating HF is mediated via MMP13. MMP13 provides a novel option when developing new therapeutics for HF treatment.
如今，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂不仅是糖尿病药物，还可用于治疗糖尿病和非糖尿病患者的慢性心力衰竭（HF），且与射血分数无关。SGLT2 抑制剂具有心脏保护作用，其背后的机制有很多种假说。然而，其潜在机制仍在很大程度上尚未被探索。在这里，我们使用斑马鱼胚胎模型来寻找新的潜在靶点，以研究 SGLT2 抑制剂减轻 HF 的作用机制。
通过化学诱导缺氧使斑马鱼胚胎产生 HF。我们使用恩格列净作为 SGLT2 抑制剂。使用视频显微镜和胚胎心脏的分数缩短（FS）计算来评估恩格列净对胚胎缺氧性 HF 的影响。还使用脑钠肽（bnp）表达的 RT-qPCR 来检测恩格列净对 HF 的影响。对胚胎总 RNA 进行转录组分析，以寻找新的潜在机制，这些机制可能有助于恩格列净对 HF 的有益作用。
恩格列净可显著减轻斑马鱼胚胎的缺氧性 HF，表现为心脏 FS 改善和 bnp 表达降低。转录组分析显示，恩格列净改善 HF 的作用伴随着基质金属蛋白酶 13a（mmp13a）表达的降低。用 MMP13 抑制剂处理缺氧诱导的胚胎可改善受损的心脏功能，与恩格列净的作用相当。MMP13 抑制剂对胚胎没有毒性。
我们的研究表明，恩格列净减轻 HF 的有利作用是通过 MMP13 介导的。MMP13 为 HF 治疗的新治疗方法提供了新的选择。
