Qian Yin1,2, Haiyan Lu1,3, Yajun Bai3, Aiju Tian1, Qiuxiang Yang1,3, Jimin Wu1, Chengzhi Yang1, Tai-Ping Fan4, Youyi Zhang1, Xiaohui Zheng3, Xiaopu Zheng2, Zijian Li1. 1. Institute of Vascular Medicine, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China. 2. Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, China. 3. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, China. 4. Angiogenesis and Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK.
Abstract
BACKGROUND AND PURPOSE: Cardiac fibrosis is a common feature of advanced coronary heart disease and is characteristic of heart disease. However, currently available drugs against cardiac fibrosis are still very limited. Here, we have assessed the role of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxylpropanoate (IDHP), a new metabolite of Danshen Dripping Pills, in cardiac fibrosis mediated by the β-adrenoceptor agonist, isoprenaline, and its underlying mechanisms. EXPERIMENTAL APPROACH: Identification of IDHP was identified by mass spectrometry, and proton and carbon nuclear magnetic resonance spectra. Myocardial collagen was quantitatively assessed with Picrosirius Red staining. Expression of mRNA for collagen was evaluated with real-time PCR. Phosphorylated and total p38 MAPK, NADPH oxidase (NOX) and superoxide dismutase (SOD) were analysed by Western blot. Generation of reactive oxygen species (ROS) generation was evaluated by dihydroethidium (DHE) fluorescent staining. NOX2 was knocked down using specific siRNA. KEY RESULTS: IDHP attenuated β-adrenoceptor mediated cardiac fibrosis in vivo and inhibited isoprenaline-induced proliferation of neonatal rat cardiac fibroblasts (NRCFs) and collagen I synthesis in vitro. Phosphorylation of p38 MAPK, which is an important mediator in the pathogenesis of isoprenaline-induced cardiac fibrosis, was inhibited by IDHP. This inhibition of phospho-p38 by IDHP was dependent on decreased generation of ROS. These effects of IDHP were abolished in NRCFs treated with siRNA for NOX2. CONCLUSIONS AND IMPLICATIONS: IDHP attenuated the cardiac fibrosis induced by isoprenaline through a NOX2/ROS/p38 pathway. These novel findings suggest that IDHP is a potential pharmacological candidate for the treatment of cardiac fibrosis, induced by β-adrenoceptor agonists.
BACKGROUND AND PURPOSE:Cardiac fibrosis is a common feature of advanced coronary heart disease and is characteristic of heart disease. However, currently available drugs against cardiac fibrosis are still very limited. Here, we have assessed the role of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxylpropanoate (IDHP), a new metabolite of Danshen Dripping Pills, in cardiac fibrosis mediated by the β-adrenoceptor agonist, isoprenaline, and its underlying mechanisms. EXPERIMENTAL APPROACH: Identification of IDHP was identified by mass spectrometry, and proton and carbon nuclear magnetic resonance spectra. Myocardial collagen was quantitatively assessed with Picrosirius Red staining. Expression of mRNA for collagen was evaluated with real-time PCR. Phosphorylated and total p38 MAPK, NADPH oxidase (NOX) and superoxide dismutase (SOD) were analysed by Western blot. Generation of reactive oxygen species (ROS) generation was evaluated by dihydroethidium (DHE) fluorescent staining. NOX2 was knocked down using specific siRNA. KEY RESULTS:IDHP attenuated β-adrenoceptor mediated cardiac fibrosis in vivo and inhibited isoprenaline-induced proliferation of neonatal rat cardiac fibroblasts (NRCFs) and collagen I synthesis in vitro. Phosphorylation of p38 MAPK, which is an important mediator in the pathogenesis of isoprenaline-induced cardiac fibrosis, was inhibited by IDHP. This inhibition of phospho-p38 by IDHP was dependent on decreased generation of ROS. These effects of IDHP were abolished in NRCFs treated with siRNA for NOX2. CONCLUSIONS AND IMPLICATIONS: IDHP attenuated the cardiac fibrosis induced by isoprenaline through a NOX2/ROS/p38 pathway. These novel findings suggest that IDHP is a potential pharmacological candidate for the treatment of cardiac fibrosis, induced by β-adrenoceptor agonists.
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