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: Xin-Hua Liu, Li-Long Pan, Hai-Yan Deng, Qing-Hui Xiong, Dan Wu, Guo-Ying Huang, Qi-Hai Gong, Yi-Zhun Zhu
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 54 Pg. 93-104 (Jan 2013) ISSN: 1873-4596 [Electronic] United States
• PMID: 23127783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• RNA, Small Interfering
• Reactive Oxygen Species
• leonurine
• Angiotensin II
• Gallic Acid
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, rat
• Extracellular Signal-Regulated MAP Kinases
• Matrix Metalloproteinase 2

Topics

• Angiotensin II (metabolism)
• Animals
• Cells, Cultured
• Down-Regulation
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblasts (drug effects, metabolism, pathology)
• Fibrosis
• Gallic Acid (administration & dosage, adverse effects, analogs & derivatives)
• Leonurus
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Myocardial Infarction (enzymology, pathology)
• Myocardium (enzymology, pathology)
• NADPH Oxidase 4
• NADPH Oxidases (antagonists & inhibitors, genetics)
• NF-kappa B (metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)