title: Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4.
abstract: 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 (10-20 μM) 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Liu
authors.forename: Li-Long
authors.initials: LL
authors.lastname: Pan
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Deng
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Xiong
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Huang
authors.forename: Qi-Hai
authors.initials: QH
authors.lastname: Gong
authors.forename: Yi-Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005707:Gallic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D031332:Leonurus; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C013587:leonurine; D000804:Angiotensin II; D005707:Gallic Acid; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2