Document Detail


Candesartan antagonizes pressure overload-evoked cardiac remodeling through Smad7 gene-dependent MMP-9 suppression.
MedLine Citation:
PMID:  22326534     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The present study was designed to investigate the underlying molecular mechanism for Angiotensin II type 1 receptor blockers (ARBs) mediated cardio-protection against pressure overload-induced cardiac remodeling with a focus on Smad7. ROCK-1, Smad3 and fibronectin expressions were increased in male C57BL/6 mice underwent transverse aortic constriction (TAC) for 2weeks. Treatment with Candesartan (2mg/kg per day) could effectively downregulate Smad3 and fibronectin accompanied by upregulating of Smad7. Further data showed that Candesartan inhibited TGF-β1 signal-induced epithelial-to-mesenchymal transition (EMT) through attenuating matrix metalloproteinases (MMP-9), such effect was abolished by knocking-down Smad7. Moreover, TAC for 2weeks caused increased collagen deposition, thickness of left ventricular anterior and posterior wall at end-diastole (LVAWD and LVPWD) and LVEF% reduction, which were reversed by treatment with Candesartan, but failed after knocking-down Smad7. In addition, LV dP/dt(max) and dP/dt(min) were increased by TAC for 2weeks, and treatment with Candesartan or Nifedipine effectively depressed the high levels of dP/dt(min) induced by TAC. However, only Candesartan-mediated protective role in improving cardiac function was suppressed by tail-vein injection of Smad7 siRNA. This study uncovered a novel role for ARBs in preventing pressure overload-induced cardiac remodeling via Smad7 upregulation, which suppressed MMP-9 expression and TGF-β1 signal-mediated EMT progress.
Authors:
Hong Yu; Gang Zhao; Hui Li; Xiaojian Liu; Shijun Wang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-03
Journal Detail:
Title:  Gene     Volume:  497     ISSN:  1879-0038     ISO Abbreviation:  Gene     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-16     Completed Date:  2012-07-18     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  7706761     Medline TA:  Gene     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  301-6     Citation Subset:  IM    
Copyright Information:
Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.
Affiliation:
Department of Pathology, Nantong University, Jiangsu Province, China. yuhongmiaomiao@163.com
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II Type 1 Receptor Blockers / pharmacology*
Animals
Benzimidazoles / pharmacology*
Cells, Cultured
Collagen / metabolism
Epithelial-Mesenchymal Transition / drug effects,  genetics,  physiology
Fibroblasts / drug effects,  metabolism,  pathology,  physiology
Fibronectins / genetics,  metabolism
Gene Knockdown Techniques / methods
Heart Ventricles / drug effects,  metabolism,  physiopathology
Male
Matrix Metalloproteinase 9 / genetics,  metabolism
Matrix Metalloproteinase Inhibitors*
Mice
Mice, Inbred C57BL
Myocytes, Cardiac / drug effects,  metabolism,  pathology,  physiology
Nifedipine / pharmacology
Pressure / adverse effects
RNA, Small Interfering / genetics
Signal Transduction / drug effects,  genetics
Smad3 Protein / genetics,  metabolism
Smad7 Protein / genetics*,  metabolism
Tetrazoles / pharmacology*
Transforming Growth Factor beta1 / antagonists & inhibitors,  metabolism
Up-Regulation / drug effects,  genetics
Ventricular Remodeling / drug effects*,  genetics*,  physiology
rho-Associated Kinases / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Benzimidazoles; 0/Fibronectins; 0/Matrix Metalloproteinase Inhibitors; 0/RNA, Small Interfering; 0/Rock1 protein, mouse; 0/Smad3 Protein; 0/Smad3 protein, mouse; 0/Smad7 Protein; 0/Smad7 protein, mouse; 0/Tetrazoles; 0/Transforming Growth Factor beta1; 21829-25-4/Nifedipine; 9007-34-5/Collagen; EC 2.7.11.1/rho-Associated Kinases; EC 3.4.24.35/Matrix Metalloproteinase 9; S8Q36MD2XX/candesartan

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