Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4

• Published in: Free radical biology & medicine Vol. 54; pp. 93 - 104
• Main Authors: Liu, Xin-Hua, Pan, Li-Long, Deng, Hai-Yan, Xiong, Qing-Hui, Wu, Dan, Huang, Guo-Ying, Gong, Qi-Hai, Zhu, Yi-Zhun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013
• Subjects: actin; angiotensin II; Angiotensin II - metabolism; Animals; Cardiac fibroblasts; cardioprotective effect; Cells, Cultured; collagen; Down-Regulation; Extracellular Signal-Regulated MAP Kinases - metabolism; fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Free radicals; Gallic Acid - administration & dosage; Gallic Acid - adverse effects; Gallic Acid - analogs & derivatives; in vitro studies; in vivo studies; infarction; Leonurine; Leonurus; Male; Matrix Metalloproteinase 2 - metabolism; metalloproteinases; mitogen-activated protein kinase; muscles; Myocardial fibrosis; Myocardial Infarction - enzymology; Myocardial Infarction - pathology; Myocardium - enzymology; Myocardium - pathology; NADPH Oxidase 4; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; NF-kappa B - metabolism; Rats; Rats, Sprague-Dawley; reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; Signal Transduction - drug effects; transcription factor NF-kappa B; NADPH oxidase 4; Cardiac fibroblasts; Myocardial fibrosis; Free radicals; Leonurine
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.10.555

In our previous studies, we have reported that leonurine, a plant phenolic alkaloid in Herba leonuri, exerted cardioprotective properties in a number of preclinical experiments. Herein, we investigated the roles and the possible mechanisms of leonurine for reducing fibrotic responses in angiotensin II (Ang II)-stimulated primary neonatal rat cardiac fibroblasts and post-myocardial infarction (MI) rats. In in vitro experiments performed in neonatal rat cardiac fibroblasts, leonurine (10–20μM) pretreatment attenuated Ang II-induced activation of extracellular signal-regulated kinase 1/2, production of intracellular reactive oxygen species (ROS), expression and activity of matrix metalloproteinase (MMP)-2/9, and expression of α-smooth muscle actin and types I and III collagen. A small interfering RNA-mediated knockdown strategy for NADPH oxidase 4 (Nox4) revealed that Nox4 was required for Ang II-induced activation of cardiac fibroblasts. In vivo studies using a post-MI model in rats indicated that administration of leonurine inhibited myocardial fibrosis while reducing cardiac Nox4 expression, ROS production, NF-κB activation, and plasma MMP-2 activity. In conclusion, our results provide the first evidence that leonurine could prevent cardiac fibrosis and the activation of cardiac fibroblasts partly through modulation of a Nox4–ROS pathway. [Display omitted] ► Leonurine inhibited Ang II-induced cardiac fibroblast activation. ► Nox4 siRNA abolished Ang II-induced fibrotic response, which was mimicked by leonurine. ► Inhibition of Nox4 expression by leonurine was involved in ERK signaling. ► Leonurine inhibited the Nox4–ROS system, accompanied by reduced myocardial fibrosis.