Xiaoliang Jiang1, Meiyu Shao2, Xue Liu1, Xing Liu1, Xu Zhang3, Yuming Wang3, Kunlun Yin4, Shuiyun Wang5, Yang Hu2, Pedro A Jose6,7, Zhou Zhou4, Fu-Jian Xu2, Zhiwei Yang1. 1. NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS & PUMC), and Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases 5 Pan Jia Yuan Nan Li, Chaoyang District Beijing 100021 P. R. China. 2. Key Lab of Biomedical Materials of Natural Macromolecules Ministry of Education Beijing Laboratory of Biomedical Materials Beijing Advanced Innovation Center for Soft Matter Science and Engineering Beijing University of Chemical Technology Beijing 100029 P. R. China. 3. Department of Hepato-Biliary-Pancreatic Surgery Henan Provincial People's Hospital People's Hospital of Zhengzhou University Zhengzhou Henan 450003 P. R. China. 4. State Key Laboratory of Cardiovascular Disease Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases Diagnostic Laboratory Service Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100037 P. R. China. 5. Department of Cardiovascular Surgery State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100037 P. R. China. 6. Department of Pharmacology and Physiology The George Washington University School of Medicine & Health Sciences Washington DC 20052 USA. 7. Department of Medicine Division of Kidney Diseases & Hypertension The George Washington University School of Medicine & Health Sciences Washington DC 20052 USA.
Abstract
Left ventricular hypertrophy and fibrosis are major risk factors for heart failure, which require timely and effective treatment. Genetic therapy has been shown to ameliorate hypertrophic cardiac damage. In this study, it is found that in mice, the dopamine D5 receptor (D5R) expression in the left ventricle (LV) progressively decreases with worsening of transverse aortic constriction-induced left ventricular hypertrophy. Then, a reversible treatment of left ventricular hypertrophy with Drd5 nucleic acids delivered by tobramycin-based hyperbranched polyaminoglycoside (SS-HPT) is studied. The heart-specific increase in D5R expression by SS-HPT/Drd5 plasmid in the early stage of left ventricular hypertrophy attenuates cardiac hypertrophy and fibrosis by preventing oxidative and endoplasmic reticulum (ER) stress and ameliorating autophagic dysregulation. By contrast, SS-HPT/Drd5 siRNA promotes the progression of left ventricular hypertrophy and accelerates the deterioration of myocardial function into heart failure. The reduction in cardiac D5R expression and dysregulated autophagy are observed in patients with hypertrophic cardiomyopathy and heart failure. The data show a cardiac-specific beneficial effect of SS-HPT/Drd5 plasmid on myocardial remodeling and dysfunction, which may provide an effective therapy of patients with left ventricular hypertrophy and heart failure.
Left ventricular hypertrophy and n>an class="Disease">fibrosis are major risk factors for heart failure, which require timely and effective treatment. Genetic therapy has been shown to ameliorate hypertrophic cardiac damage. In this study, it is found that in mice, the dopamine D5 receptor (D5R) expression in the left ventricle (LV) progressively decreases with worsening of transverse aortic constriction-induced left ventricular hypertrophy. Then, a reversible treatment of left ventricular hypertrophy with Drd5 nucleic acids delivered by tobramycin-based hyperbranched polyaminoglycoside (SS-HPT) is studied. The heart-specific increase in D5R expression by SS-HPT/Drd5 plasmid in the early stage of left ventricular hypertrophy attenuates cardiac hypertrophy and fibrosis by preventing oxidative and endoplasmic reticulum (ER) stress and ameliorating autophagic dysregulation. By contrast, SS-HPT/Drd5 siRNA promotes the progression of left ventricular hypertrophy and accelerates the deterioration of myocardial function into heart failure. The reduction in cardiac D5R expression and dysregulated autophagy are observed in patients with hypertrophic cardiomyopathy and heart failure. The data show a cardiac-specific beneficial effect of SS-HPT/Drd5 plasmid on myocardial remodeling and dysfunction, which may provide an effective therapy of patients with left ventricular hypertrophy and heart failure.
Authors: David Bode; Diana Lindner; Michael Schwarzl; Dirk Westermann; Peter Deissler; Uwe Primessnig; Niklas Hegemann; Lothar A Blatter; Sophie van Linthout; Carsten Tschöpe; Felix Schoenrath; Sajjad Soltani; Christof Stamm; Volker Duesterhoeft; Natale Rolim; Ulrik Wisløff; Christoph Knosalla; Volkmar Falk; Burkert M Pieske; Frank R Heinzel; Felix Hohendanner Journal: J Mol Cell Cardiol Date: 2019-04-18 Impact factor: 5.000
Authors: Stefan Hein; Eyal Arnon; Sawa Kostin; Markus Schönburg; Albrecht Elsässer; Victoria Polyakova; Erwin P Bauer; Wolf-Peter Klövekorn; Jutta Schaper Journal: Circulation Date: 2003-02-25 Impact factor: 29.690