Identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. The in vivo pathological cardiac hypertrophy models were induced by pressure-overload and angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological cardiac hypertrophy, but not in swimming exercise-induced physiological cardiac hypertrophy in mice. BMP4 expression also increased in Ang II-induced cardiomyocyte hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II-induced cardiomyocyte hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte hypertrophy and apoptosis was through increasing NADPH oxidase 4 expression and reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload-induced cardiac hypertrophy in mice in vivo. The plasma BMP4 level of heart failure patients was increased compared with that of subjects without heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological cardiac hypertrophy.

译文

:确定介导病理性心脏肥大的关键因素对于制定预防心力衰竭的策略至关重要。骨形态发生蛋白4(BMP4)是机械敏感和促炎基因。在这项研究中,我们调查了BMP4在实验性病理性心肌肥大中在心肌肥大,细胞凋亡和纤维化中的作用。通过压力超负荷和血管紧张素(Ang)II恒定输注诱导小鼠体内病理性心肌肥大模型,并通过将Ang II暴露于培养的心肌细胞诱导体外模型。在压力超负荷,Ang II持续输注引起的病理性心肌肥大中,BMP4的表达增加,但在游泳运动引起的小鼠生理性心肌肥大中则没有。在体外,Ang II诱导的心肌肥大中BMP4表达也增加。反过来,BMP4诱导心肌肥大,凋亡和心脏纤维化,而这些病理后果被BMP4抑制剂头蛋白和DMH1的治疗所抑制。此外,Ang II诱导的心肌肥大被BMP4抑制剂抑制。 BMP4诱导心肌肥大和凋亡的潜在机制是通过增加NADPH氧化酶4的表达和活性氧依赖性途径。慢病毒介导的BMP4的过表达在培养的心肌细胞中概括了肥大和细胞凋亡。 BMP4抑制剂DMH1在体内抑制了压力超负荷引起的心脏肥大。与没有心力衰竭的受试者相比,心力衰竭患者的血浆BMP4水平升高。总之,我们得出结论,BMP4是病理性心脏肥大的介体和新的治疗靶标。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录