Captopril attenuates TAC-induced heart failure via inhibiting Wnt3a/β-catenin and Jak2/Stat3 pathways
Captopril attenuates TAC-induced heart failure via inhibiting Wnt3a/β-catenin and Jak2/Stat3 pathways
复制标题
DOI：
10.1016/j.biopha.2019.108780
复制
发表时间：
2019-05-01
影响因子：
7.5
通讯作者：
Li, Fang
中科院分区：
文献类型：
--
作者：
Zhang, Yu;Zhang, Ling;Li, Fang
卡托普利(Captopril，Cap)作为血管紧张素转换酶抑制剂(ACEI)，常用于治疗高血压和某些类型的充血性心力衰竭。然而，有关Cap是否对横断性主动脉缩窄(TAC)诱导的心肌细胞凋亡具有保护作用的研究报道较少。本研究旨在探讨青蒿琥酯对压力超负荷所致心肌细胞凋亡的可能机制。结果表明，卡铂显著降低心脏/体重比(HBWR)。超声心动图显示，CAP可明显改善TAC小鼠的心功能，缩小升主动脉内径(ASCAO)。酶联免疫吸附试验(EL ISA)结果显示，Cap还能显著降低血浆N末端B型利钠肽原(NT-proBNP)、心钠素(ANP)、肿瘤坏死因子-α(TNF-α)和白介素6(IL-6)水平。苏木精-伊红(H&E)染色和Masson‘s三色染色显示，Cap治疗后心脏病理改变和纤维化均有所改善。此外，末端脱氧核苷酸转移酶介导的三磷酸脱氧尿苷缺口末端标记(TUNEL)染色结果显示，Cap治疗还能显著抑制心肌细胞凋亡。Western Blot结果显示，Cap明显降低裂解的Capase-3、Bax、磷酸化JAK2(p-JAK2)、磷酸化STAT3(p-STAT3)、Wnt3a和β-catenin蛋白的表达，并上调Bcl2的表达。结论：Cap对TAC诱导的心肌细胞凋亡具有保护作用，其机制可能与抑制Wnt3a/β-catenin信号通路有关。CAP还通过抑制JAK2/STAT3通路减轻TAC诱导的心肌肥厚。
Captopril (Cap) as angiotensin-converting enzyme inhibitor (ACEi) is commonly used to treat hypertension and some types of congestive heart failure. However, few studies reported on whether Cap exerts a protective effect on myocardial apoptosis induced by transverse aortic constriction (TAC). This study aimed at investigating the possible mechanism of Cap on myocardial apoptosis induced by pressure overload. Results showed that Cap significantly decreased heart-to-body weight ratios (HBWR). Cap markedly improved cardiac function, and reduced inner diameter of ascending aorta (Asc Ao) in TAC mice as shown by echocardiography. Enzyme-linked immunosorbent assay (ELISA) results demonstrated that Cap treatment also markedly decreased the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Cardiac pathological changes and fibrosis have been improved after Cap treatment as shown by hematoxylin-eosin (H&E) staining and Masson's trichrome staining. Moreover, Terminal deoxynucleotidyl transferase-mediated dexoxyuridine triphosphate nick-end labeling (TUNEL) staining result indicated Cap treatment also significantly inhibited cardiac apoptosis. Western Blot results showed that Cap obviously decreased the expression of cleaved capase-3, Bax, phosphorylated Jak2 (p-Jak2), phosphorylated Stat3 (p-Stat3), Wnt3a and beta-catenin proteins, as well as increased Bcl-2 expression. In conclusion, Cap showed a protective effect on TAC-induced cardiac apoptosis, which could be attributed to the inhibition of Wnt3a/beta-catenin signaling pathway. Cap also attenuated myocardial hypertrophy induced by TAC via suppression of Jak2/Stat3 pathway.