Yuan Xun, Pan Li, Zhang Chi, Zhu Qiulian, Huang Zexin, Qin Yuan, Zhang Guiping, Feng Zhimei, Yang Caixian, Hou Ning
The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, NMPA Key Laboratory for Clinical Research and Evaluation of Drug for Thoracic Diseases, Guangzhou Medical University, Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, Guangzhou Medical University, Guangzhou, China.
Front Pharmacol. 2024 Nov 27;15:1499542. doi: 10.3389/fphar.2024.1499542. eCollection 2024.
Empagliflozin (EMPA) is an SGLT-2 inhibitor that can control hyperglycemia. Clinical trials have indicated its cardio-protective effects against cardiac remodeling in diabetes or non-diabetes patients. However, the underlying molecular mechanisms of EMPA's cardio-protective effects remain elusive.
We evaluated whether the EMPA attenuated the pressure-overload-induced cardiac hypertrophy by inhibiting the Wnt/β-catenin pathway. Furthermore, the effects of the EMPA on a mouse model of transverse aortic constriction (TAC) induced cardiac hypertrophy was also evaluated. Mice were administrated with 0.5% CMC-Na as a vehicle or EMPA (10 mg/kg/day, daily, throughout the study) by intragastric gavage.
The echocardiography and histologic morphological analyses revealed that EMPA attenuated TAC-induced cardiac hypertrophy. Moreover, it also ameliorated TAC-induced cardiac fibrosis and decreased the cell size of the cardiomyocytes in isolated adult cardiomyocytes. Molecular mechanism analysis revealed that the EMPA reduced the TAC-induced enhanced expression of the Wnt/β-catenin pathway . For assessments, isolated neonatal rat cardiomyocytes (NRCMs) were treated with Angiotensin II (AngII) and EMPA; the results showed that in the absence of EMPA, the expression of the Wnt/β-catenin pathway was enhanced. In the trans-genetic heterozygous β-catenin deletion mice, EMPA attenuated TAC-induced cardiac remodeling by reducing the Wnt/β-catenin pathway. In addition, molecular docking analysis indicated that EMPA interacts with FZD4 to inhibit the TAC and AngII induced Wnt/β-catenin pathway in cardiomyocytes.
Our study illustrated that EMPA might directly interact with FZD4 to inhibit the TAC and AngII-induced activation of the Wnt/β-catenin pathway to attenuate the adverse cardiac remodeling.
恩格列净（EMPA）是一种可控制高血糖的钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂。临床试验表明其对糖尿病或非糖尿病患者的心脏重塑具有心脏保护作用。然而，EMPA心脏保护作用的潜在分子机制仍不清楚。
我们评估了EMPA是否通过抑制Wnt/β-连环蛋白信号通路来减轻压力超负荷诱导的心脏肥大。此外，还评估了EMPA对横向主动脉缩窄（TAC）诱导的小鼠心脏肥大模型的影响。小鼠通过灌胃给予0.5%羧甲基纤维素钠（CMC-Na）作为载体或EMPA（10mg/kg/天，在整个研究过程中每天给药）。
超声心动图和组织形态学分析显示，EMPA减轻了TAC诱导的心脏肥大。此外，它还改善了TAC诱导的心脏纤维化，并减小了分离的成年心肌细胞的细胞大小。分子机制分析显示，EMPA降低了TAC诱导的Wnt/β-连环蛋白信号通路的增强表达。为了进行评估，用血管紧张素II（AngII）和EMPA处理分离的新生大鼠心肌细胞（NRCMs）；结果表明，在没有EMPA的情况下，Wnt/β-连环蛋白信号通路的表达增强。在转基因杂合β-连环蛋白缺失小鼠中，EMPA通过减少Wnt/β-连环蛋白信号通路减轻了TAC诱导的心脏重塑。此外，分子对接分析表明，EMPA与卷曲蛋白4（FZD4）相互作用，抑制TAC和AngII诱导的心肌细胞中Wnt/β-连环蛋白信号通路。
我们的研究表明，EMPA可能直接与FZD4相互作用，抑制TAC和AngII诱导的Wnt/β-连环蛋白信号通路的激活，从而减轻不良心脏重塑。
