title: Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload.
abstract: Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis.
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, PR China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, PR China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, PR China.
authors.forename: Dachun
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, PR China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China.
authors.forename: Tichao
authors.initials: T
authors.lastname: Shan
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, PR China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China; Department of Emergency, Qilu Hospital of Shandong University, Jinan, PR China. Electronic address: chen919085@163.com.
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, PR China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, PR China. Electronic address: wdwu55@163.com.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wu
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005355:Fibrosis / Q000503:physiopathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017382:Reactive Oxygen Species; D011794:Quercetin; C003377:taxifolin; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: Cardiac hypertrophy; Fibrosis; MAPKs; Oxidative stress; Smad signaling; Taxifolin