Department of Drug Clinical Trial, Guangdong Second Provincial General Hospital, Guangzhou, China.
Laboratory of Vascular Biology, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China.
J Cell Mol Med. 2019 Jun;23(6):4196-4207. doi: 10.1111/jcmm.14308. Epub 2018 Dec 26.
Rutaecarpine attenuates hypertensive cardiac hypertrophy in the rats with abdominal artery constriction (AAC); however, its mechanism of action remains largely unknown. Our previous study indicated that NADPH oxidase 4 (Nox4) promotes angiotensin II (Ang II)-induced cardiac hypertrophy through the pathway between reactive oxygen species (ROS) and a disintegrin and metalloproteinase-17 (ADAM17) in primary cardiomyocytes. This research aimed to determine whether the Nox4-ROS-ADAM17 pathway is involved in the protective action of rutaecarpine against hypertensive cardiac hypertrophy. AAC-induced hypertensive rats were adopted to evaluate the role of rutaecarpine in hypertensive cardiac hypertrophy. Western blotting and real-time PCR were used to detect gene expression. Rutaecarpine inhibited hypertensive cardiac hypertrophy in AAC-induced hypertensive rats. These findings were confirmed by the results of in vitro experiments that rutaecarpine significantly inhibited Ang II-induced cardiac hypertrophy in primary cardiomyocytes. Likewise, rutaecarpine significantly suppressed the Nox4-ROS-ADAM17 pathway and over-activation of extracellular signal-regulated kinase (ERK) 1/2 pathway in the left ventricle of AAC-induced hypertensive rats and primary cardiomyocytes stimulated with Ang II. The inhibition of Nox4-ROS-ADAM17 pathway and over-activation of ERK1/2 might be associated with the beneficial role of rutaecarpine in hypertensive cardiac hypertrophy, thus providing additional evidence for preventing hypertensive cardiac hypertrophy with rutaecarpine.
荷叶碱可减轻腹主动脉缩窄（AAC）大鼠的高血压性心肌肥厚；但其作用机制尚不清楚。我们之前的研究表明，NADPH 氧化酶 4（Nox4）通过活性氧（ROS）和解整合素金属蛋白酶 17（ADAM17）之间的途径促进血管紧张素 II（Ang II）诱导的心肌肥厚，在原代心肌细胞中。本研究旨在确定 Nox4-ROS-ADAM17 途径是否参与荷叶碱对高血压性心肌肥厚的保护作用。采用 AAC 诱导的高血压大鼠来评估荷叶碱在高血压性心肌肥厚中的作用。采用 Western blot 和实时 PCR 检测基因表达。荷叶碱抑制 AAC 诱导的高血压大鼠的高血压性心肌肥厚。体外实验结果证实了这一发现，荷叶碱显著抑制了原代心肌细胞中 Ang II 诱导的心肌肥厚。同样，荷叶碱显著抑制了 AAC 诱导的高血压大鼠左心室和 Ang II 刺激的原代心肌细胞中 Nox4-ROS-ADAM17 途径和细胞外信号调节激酶（ERK）1/2 途径的过度激活。Nox4-ROS-ADAM17 途径的抑制和 ERK1/2 的过度激活可能与荷叶碱在高血压性心肌肥厚中的有益作用有关，从而为荷叶碱预防高血压性心肌肥厚提供了更多证据。
