Tang Kecheng, Zhong Bin, Luo Qingman, Liu Qiao, Chen Xin, Cao Dayan, Li Xiaohui, Yang Shengqian
Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, 400038, China.
Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, 400038, China; Chongqing Engineering Research Center for Pharmacodynamics Evaluation, College of Pharmacy, Army Medical University, Chongqing, 400038, China.
Eur J Pharmacol. 2022 Jul 15;927:175022. doi: 10.1016/j.ejphar.2022.175022. Epub 2022 May 13.
Phillyrin, a well-known natural compound from the dried fruits of Forsythia suspensa (Thunb.) Vahl., has shown anti-inflammatory, antioxidant and anti-virus activities as well as renal protective effects on diabetic nephropathy. In this study, we investigated whether phillyrin attenuated cardiac hypertrophy induced by catecholamine in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in C57BL/6 mice by subcutaneous injection of norepinephrine (NE, a key catecholamine), and in rat cardiomyoblasts (H9c2) by stimulation with NE in vitro. Our results showed that administration of phillyrin (100 mg/kg, i.p. for 15 days) significantly improved cardiac function, histopathological changes, cardiac hypertrophy and decreased the upregulated hypertrophic markers (ANP, BNP, and β-MHC). Moreover, treatment with phillyrin obviously reduced the infiltration of the CD68 positive macrophages and the mRNA expression of proinflammatory genes (IL-1β, IL-6, and TNF-α) in left ventricular tissue. In addition, treatment with phillyrin markedly inhibited the phosphorylation of p38 MAPK, ERK1/2, AKT, and NF-κB p65 in heart tissues. Furthermore, in NE-treated H9c2 cells, pretreatment with phillyrin clearly attenuated cardiomyocyte hypertrophy, reduced ROS production and inhibited the phosphorylation of p38 MAPK, ERK1/2, AKT, and NF-κB p65 in vitro. Collectively, our results demonstrate that phillyrin effectively alleviates NE-induced cardiac hypertrophy and inflammatory response by suppressing p38 MAPK/ERK1/2 and AKT/NF-κB signaling pathways.
连翘苷是一种从连翘干燥果实中提取的著名天然化合物，已显示出抗炎、抗氧化和抗病毒活性以及对糖尿病肾病的肾脏保护作用。在本研究中，我们调查了连翘苷是否在体内和体外减轻儿茶酚胺诱导的心脏肥大，并探讨了其潜在机制。通过皮下注射去甲肾上腺素（NE，一种关键的儿茶酚胺）在C57BL/6小鼠中诱导心脏肥大，并在体外通过NE刺激大鼠心肌成纤维细胞（H9c2）诱导心脏肥大。我们的结果表明，给予连翘苷（100mg/kg，腹腔注射15天）可显著改善心脏功能、组织病理学变化、心脏肥大，并降低上调的肥大标志物（心房钠尿肽、脑钠肽和β-肌球蛋白重链）。此外，连翘苷治疗明显减少了左心室组织中CD68阳性巨噬细胞的浸润和促炎基因（白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α）的mRNA表达。此外，连翘苷治疗显著抑制了心脏组织中p38丝裂原活化蛋白激酶、细胞外信号调节激酶1/2、蛋白激酶B和核因子-κB p65的磷酸化。此外，在NE处理的H9c2细胞中，连翘苷预处理明显减轻了心肌细胞肥大，减少了活性氧的产生，并在体外抑制了p38丝裂原活化蛋白激酶、细胞外信号调节激酶1/2、蛋白激酶B和核因子-κB p65的磷酸化。总的来说，我们的结果表明，连翘苷通过抑制p38丝裂原活化蛋白激酶/细胞外信号调节激酶1/2和蛋白激酶B/核因子-κB信号通路有效减轻NE诱导的心脏肥大和炎症反应。
