Li He, Gong Zhi-Jun, He Yun, Huang Jing-Jing, Jiang Yu-Ning, Liu Ya-Yang, Zhu Yao, Jiang Wei-Min
Department of Cardiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China.
Department of Cardiology, Huai'an Hospital of Chinese Medicine, Huai'an, China.
Evid Based Complement Alternat Med. 2020 Dec 14;2020:7532892. doi: 10.1155/2020/7532892. eCollection 2020.
Heart failure (HF) has been known as a global health problem, and cardiac remodeling plays an essential role in the development of HF. We hypothesized that YQWY decoction might exert a cardioprotective effect against myocardium inflammation, fibrosis, and apoptosis via activating the interleukin-10 (IL-10)/Stat3 signaling pathway. To test this hypothesis, the HF model in rats was established by pressure overload through the minimally invasive transverse aortic constriction (MTAC). Echocardiography was performed to assess the left ventricular function of rats. Myocardial fibrosis in rats was observed by Masson and Picrosirius red staining, and the degree of myocardial apoptosis was detected via TUNEL staining. In addition, expression levels of IL-10, tumor necrosis factor- (TNF-), Stat3 (P-Stat3), P65 (P-P65), CD68, collagen I, TGF-, CTGF, Bax, Bcl-2, cleaved caspase-3, and PARP in rat serum and myocardium samples were examined by ELISA, western blot, and immunohistochemistry, respectively. YQWY decoction treatment significantly improved left ventricular function in HF rats, especially in those of the high-dose group (LVEF%: 51.29 ± 5.876 vs. 66.02 ± 1.264, < 0.01;, LVFS%: 27.75 ± 3.757 vs. 37.76 ± 1.137, < 0.01). Furthermore, YQWY decoction markedly inhibited MTAC-induced myocardial fibrosis as evidenced by downregulated collagen I, TGF-, and CTGF in myocardium and alleviated apoptosis (downregulated caspase-3 and PARP and increased Bcl-2/Bax ratio in cardiomyocytes). In addition, YQWY decoction decreased the level of the proinflammatory cytokine TNF- in both circulating blood and myocardium and attenuated infiltration of inflammatory cells in heart tissue from HF rats. Most importantly, YQWY decoction suppressed MTAC-induced NF-B activation and phosphorylated Stat3 by upregulating IL-10 in rat heart tissues. Our study showed that YQWY decoction could attenuate MTAC-induced myocardial inflammation, fibrosis, apoptosis, and reverse the impairment of cardiac function in rats by activating the IL-10/Stat3 signaling pathway and improving myocardium remodeling. Our findings suggested a therapeutic potential of YQWY decoction in HF.
心力衰竭（HF）一直是一个全球性的健康问题，而心脏重塑在HF的发展过程中起着至关重要的作用。我们推测，益气养阴活血方可能通过激活白细胞介素-10（IL-10）/信号转导和转录激活因子3（Stat3）信号通路，对心肌炎症、纤维化和细胞凋亡发挥心脏保护作用。为了验证这一假设，通过微创横断主动脉缩窄术（MTAC）造成压力超负荷，建立大鼠HF模型。采用超声心动图评估大鼠左心室功能。通过Masson染色和天狼星红染色观察大鼠心肌纤维化情况，采用TUNEL染色检测心肌细胞凋亡程度。此外，分别采用酶联免疫吸附测定（ELISA）、蛋白质免疫印迹法（western blot）和免疫组织化学法检测大鼠血清和心肌样本中IL-10、肿瘤坏死因子-α（TNF-α）、Stat3（磷酸化Stat3）、P65（磷酸化P65）、CD68、Ⅰ型胶原、转化生长因子-β（TGF-β）、结缔组织生长因子（CTGF）、Bax、Bcl-2、裂解的半胱天冬酶-3（cleaved caspase-3）和聚（ADP-核糖）聚合酶（PARP）的表达水平。益气养阴活血方治疗显著改善了HF大鼠的左心室功能，尤其是高剂量组（左心室射血分数[LVEF%]：51.29±5.876 vs. 66.02±1.264，P<0.01；左心室短轴缩短率[LVFS%]：27.75±3.757 vs. 37.76±1.137，P<0.01）。此外，益气养阴活血方显著抑制了MTAC诱导的心肌纤维化，表现为心肌中Ⅰ型胶原、TGF-β和CTGF表达下调，并减轻了细胞凋亡（心肌细胞中裂解的半胱天冬酶-3和PARP表达下调，Bcl-2/Bax比值升高）。此外，益气养阴活血方降低了循环血液和心肌中促炎细胞因子TNF-α的水平，并减轻了HF大鼠心脏组织中炎性细胞的浸润。最重要的是，益气养阴活血方通过上调大鼠心脏组织中的IL-10，抑制了MTAC诱导的核因子-κB（NF-κB）激活和Stat3磷酸化。我们的研究表明，益气养阴活血方可以减轻MTAC诱导的心肌炎症、纤维化、细胞凋亡，并通过激活IL-10/Stat3信号通路和改善心肌重塑来逆转大鼠心脏功能的损害。我们的研究结果提示益气养阴活血方在HF治疗中具有潜在的应用价值。
