PDF(Pubmed)
Abstract：
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular diastolic dysfunction and increased filling pressure. Currently, however, there is no evidence on effective pharmacotherapy for HFpEF. In this study, we aimed to investigate the therapeutic effect of total xanthones extracted from Gentianella acuta (TXG) on HFpEF by establishing an high-fat diet (HFD) + L-NAME-induced mouse model. Echocardiography was employed to assess the impact of TXG on the cardiac function in HFpEF mice. Haematoxylin and eosin staining, wheat germ agglutinin staining, and Masson\'s trichrome staining were utilized to observe the histopathological changes following TXG treatment. The results demonstrated that TXG alleviated HFpEF by reducing the expressions of genes associated with myocardial hypertrophy, fibrosis and apoptosis. Furthermore, TXG improved cardiomyocyte apoptosis by inhibiting the expression of apoptosis-related proteins. Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients.
摘要：
射血分数保留的心力衰竭（HFpEF）是一种临床综合征，其特征是由左心室舒张功能障碍和充盈压升高引起的肺和全身充血。目前,然而,没有证据表明HFpEF的有效药物治疗.在这项研究中,我们旨在通过建立高脂饮食（HFD）L-NAME诱导的小鼠模型，研究龙胆总黄吨酮（TXG）对HFpEF的治疗作用。超声心动图用于评估TXG对HFpEF小鼠心功能的影响。苏木精和伊红染色，小麦胚芽凝集素染色，用Masson三色染色观察TXG治疗后的组织病理学变化。结果表明，TXG通过降低心肌肥厚相关基因的表达减轻HFpEF，纤维化和凋亡。此外，TXG通过抑制凋亡相关蛋白的表达改善心肌细胞凋亡。机制研究表明，TXG可以激活需要肌醇的酶1α（IRE1α）/X-box结合蛋白1（Xbp1s）信号通路，但是使用IRE1α抑制剂STF083010或siRNA-IRE1α敲低IRE1α会损害TXG改善HFpEF模型中心脏重塑的能力。总之,TXG减轻心肌肥厚，通过激活IRE1α/Xbp1s信号通路，提示其对HFpEF患者的潜在有益作用。
