Shi Yu Jiao, Yang Chen Guang, Qiao Wen Bo, Liu Yong Cheng, Liu Si Yu, Dong Guo Ju
Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
Department of Cardiovascular Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China; National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
Eur J Pharmacol. 2023 Dec 15;961:176170. doi: 10.1016/j.ejphar.2023.176170. Epub 2023 Nov 7.
Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3β (GSK-3β) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-β1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.
射血分数保留的心力衰竭（HFpEF）是一种与复杂病理机制相关的多方面综合征。沙库巴曲缬沙坦（Sac/val）已在HFpEF治疗中显示出治疗效果。然而，需要更多研究来阐明其药理机制。因此，本研究旨在探讨Sac/val对HFpEF大鼠的潜在治疗作用及其潜在的分子机制。在本研究中，通过给自发性高血压大鼠喂食富含脂肪、盐和糖的饮食并注射链脲佐菌素诱导HFpEF大鼠模型。随后，以18mg/kg的日剂量给它们施用Sac/val。最后，使用超声心动图评估心脏结构和功能；采用苏木精-伊红染色和Masson三色染色评估病理变化；进行定量实时聚合酶链反应和蛋白质免疫印迹分析以测定相关mRNA和蛋白质的表达。Sac/val治疗减轻了HFpEF大鼠的左心室（LV）重构和舒张功能障碍，这可能与其抗炎、抗肥厚和抗纤维化作用有关。机制上，Sac/val可能通过下调细胞粘附分子（细胞间粘附分子-1（ICAM-1）和血管内皮细胞粘附分子-1（VCAM-1））的表达来抑制炎症。此外，它阻断糖原合酶激酶3β（GSK-3β）的磷酸化以防止心肌细胞肥大。此外，它通过抑制转化生长因子-β1（TGF-β1）/Smads信号通路有效抑制心肌纤维化。我们的研究结果表明，Sac/val改善了LV重构和舒张功能障碍，这可能归因于其抗炎、抗肥厚和抗纤维化作用。这些结果为Sac/val在HFpEF患者中的临床应用提供了可靠的理论依据。
