芪参益气滴丸对射血分数保留型心力衰竭小鼠的治疗作用

Therapeutic effect of QiShenYiQi Dripping Pills on mice with heart failure with preserved ejection fraction

射血分数保留型心力衰竭(heart failure with preserved ejection fraction,HFpEF)约占心衰患者的一半数量,其特征除了心衰的典型特征如心肌僵硬、心脏舒张功能损伤等,最主要的特征是左心室射血正常,因此也给HFpEF的临床诊断增加了难度。芪参益气滴丸(QiShenYiQi Dripping Pills,QSYQ)是经中国食品药品监督管理局(CFDA)批准的标准化中药制剂,许多基础及临床研究均已证明QSYQ在治疗射血分数降低型心力衰竭中的有效性和安全性,然而QSYQ在HFpEF中的作用机制尚未明确。本文利用经典造模方法即高脂食物(high fat diet,HFD)和含N-硝基-L-精氨酸甲酯盐酸盐(L-NAME,0.5 g·L^(-1),pH=7.4)的饮用水喂食C57BL/6N雄性小鼠构建HFpEF模型(实验获得合肥工业大学动物伦理委员会批准,批准号为HFUT20220921002),在第8周,小鼠分别给药:(1)恩格列净(empagliflozin)、(2)低剂量QSYQ(LQ)、(3)高剂量QSYQ(HQ)、(4)恩格列净联用低剂量QSYQ(ELQ),连续给药4周,实验过程中记录小鼠的体重,实验结束后对小鼠进行超声心动检测、血压检测、葡萄糖耐量检测及评估小鼠运动情况,利用病理实验和生化实验检测小鼠心脏纤维化、肝脏纤维化及血清生化指标等,利用RNAseq测序对小鼠心脏进行RNAseq检测。结果表明,QSYQ及联用恩格列净均能够显著降低HFpEF小鼠体重,改善小鼠心脏舒张功能障碍和高血压,改善葡萄糖耐量异常并增强小鼠运动能力。在生化和分子水平上,QSYQ能够降低心肌细胞横截面积和减少心脏胶原蛋白含量进而减轻心肌肥大和纤维化表型,同时改善HFpEF小鼠机体脂质代谢紊乱。进一步地,小鼠心脏RNAseq结果表明,QSYQ改善HFpEF的功能可能与调控肌钙集蛋白1(calsequestrin 1,Casq1)有关。综上,本研究表明QSYQ能够显著改善HFpEF相关的心脏功能障碍和代谢紊乱,为HFpEF的临床治疗提供了一定实验数据支持。

Heart failure with preserved ejection fraction(HFpEF)accounts for about half of the number of patients with heart failure.In addition to the typical features of heart failure such as myocardial stiffness and diastolic function impairment,the key characteristic of HFpEF is the normal left ventricular ejection fraction,which increases the difficulty of clinical diagnosis.QiShenYiQi Dripping Pills(QSYQ)is a standardized traditional Chinese medicine approved by the China Food and Drug Administration(CFDA),and many clinical studies have demonstrated the efficacy and safety of QSYQ in the treatment of heart failure with reduced ejection fraction,but the role of QSYQ in HFpEF has not been clarified.In this paper,high fat diet(HFD)and drinking water containing N-nitro-L-arginine methyl ester(L-NAME,0.5 g·L^(-1),pH=7.4)were used in C57BL/6N male mice to construct the classical HFpEF model(the experiment was approved by the Animal Ethics Committee of Hefei University of Technology,the approval number is HFUT20220921002),and at the 8^(th)week,the mice were dosed with(1)empagliflozin,(2)low-dose QSYQ(LQ),(3)high-dose QSYQ(HQ),(4)empagliflozin plus low-dose QSYQ(ELQ)for 4 weeks,the body weight of the mice was recorded during the experiment,echocardiography,blood pressure and glucose tolerance were detected and the exercise capacity of mice was evaluated,and pathological and biochemical experiments were used to detect cardiac fibrosis,liver fibrosis and serum biochemical indexes in mice,RNAseq assay was performed with mice heart tissues.The results showed that QSYQ as well as QSYQ+empagliflozin could significantly reduce the body weight,improve diastolic function and hypertension,improve glucose tolerance and enhance exercise ability of HFpEF mice.At the biochemical and molecular levels,QSYQ and QSYQ+empagliflozin can reduce the cross-sectional area of cardiomyocytes and reduce cardiac collagen contents,thereby alleviating myocardial hypertrophy and fibrotic phenotypes,and improve metabolic disorders.The RNAseq results suggest that the function of QSYQ in improving HFpEF may be related to calsequestrin 1.In conclusion,this study shows that QSYQ and QSYQ+empagliflozin can significantly improve HFpEF-related cardiac dysfunction and metabolic disorders,which provides a theoretical basis for the clinical treatment of HFpEF.