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Article: Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling
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TitleSmad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling
 
AuthorsHuang, XR3
Chung, ACK3
Yang, F2
Yue, W2
Deng, C1
Lau, CP2
Tse, HF2
Lan, HY3
 
KeywordsAngiotensin II
Cardiac remodeling
Hypertension
Smad3
TGF-β
 
Issue Date2010
 
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://hyper.ahajournals.org/
 
CitationHypertension, 2010, v. 55 n. 5, p. 1165-1171 [How to Cite?]
DOI: http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.147611
 
AbstractAlthough Smad3 is a key mediator of fibrosis, the functional role of Smad3 in hypertensive cardiovascular disease remains unclear. The present study tested the hypothesis that angiotensin II may activate the transforming growth factor-β/Smad3 pathway to mediate hypertensive cardiac remodeling in Smad3 knockout (KO) and wild-type mice by subcutaneous angiotensin II infusion and in the primary culture of Smad3 KO cardiac fibroblasts. Fourteen days after angiotensin II infusion, both Smad3 KO and wild-type mice developed equal levels of high blood pressure. However, hypertensive cardiac fibrosis and inflammation were developed in Smad3 wild-type but not in Smad3 KO mice. This was demonstrated by the findings that mice lacking Smad3 were protected against a fall in left ventricular ejection fraction (P<0.05), an increase in left ventricular mass (P<0.05), and the development of cardiac fibrosis and inflammation, including upregulation of transforming growth factor-β1, connective tissue growth factor, collagen I/III, α-smooth muscle actin, interleukin 1β, tumor necrosis factor-α, monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and an increase in macrophage and T-cell infiltration in left ventricular tissues (all P<0.01, respectively). Additional studies in vitro also revealed that angiotensin II-induced cardiac fibrosis and inflammation were prevented in Smad3 KO cardiac fibroblasts. Inactivation of both Smad3 and nuclear factor κB/p65 signaling pathways was a key mechanism by which Smad3 KO mice were protected from angiotensin II-mediated hypertensive cardiac remodeling. In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease. Copyright © 2010 American Heart Association. All rights reserved.
 
Descriptionlink_to_OA_fulltext
 
ISSN0194-911X
2013 Impact Factor: 7.632
2013 SCImago Journal Rankings: 3.702
 
DOIhttp://dx.doi.org/10.1161/HYPERTENSIONAHA.109.147611
 
ISI Accession Number IDWOS:000276672500019
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorHuang, XR
 
dc.contributor.authorChung, ACK
 
dc.contributor.authorYang, F
 
dc.contributor.authorYue, W
 
dc.contributor.authorDeng, C
 
dc.contributor.authorLau, CP
 
dc.contributor.authorTse, HF
 
dc.contributor.authorLan, HY
 
dc.date.accessioned2011-07-27T01:30:12Z
 
dc.date.available2011-07-27T01:30:12Z
 
dc.date.issued2010
 
dc.description.abstractAlthough Smad3 is a key mediator of fibrosis, the functional role of Smad3 in hypertensive cardiovascular disease remains unclear. The present study tested the hypothesis that angiotensin II may activate the transforming growth factor-β/Smad3 pathway to mediate hypertensive cardiac remodeling in Smad3 knockout (KO) and wild-type mice by subcutaneous angiotensin II infusion and in the primary culture of Smad3 KO cardiac fibroblasts. Fourteen days after angiotensin II infusion, both Smad3 KO and wild-type mice developed equal levels of high blood pressure. However, hypertensive cardiac fibrosis and inflammation were developed in Smad3 wild-type but not in Smad3 KO mice. This was demonstrated by the findings that mice lacking Smad3 were protected against a fall in left ventricular ejection fraction (P<0.05), an increase in left ventricular mass (P<0.05), and the development of cardiac fibrosis and inflammation, including upregulation of transforming growth factor-β1, connective tissue growth factor, collagen I/III, α-smooth muscle actin, interleukin 1β, tumor necrosis factor-α, monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and an increase in macrophage and T-cell infiltration in left ventricular tissues (all P<0.01, respectively). Additional studies in vitro also revealed that angiotensin II-induced cardiac fibrosis and inflammation were prevented in Smad3 KO cardiac fibroblasts. Inactivation of both Smad3 and nuclear factor κB/p65 signaling pathways was a key mechanism by which Smad3 KO mice were protected from angiotensin II-mediated hypertensive cardiac remodeling. In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease. Copyright © 2010 American Heart Association. All rights reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.descriptionlink_to_OA_fulltext
 
dc.identifier.citationHypertension, 2010, v. 55 n. 5, p. 1165-1171 [How to Cite?]
DOI: http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.147611
 
dc.identifier.doihttp://dx.doi.org/10.1161/HYPERTENSIONAHA.109.147611
 
dc.identifier.epage1171
 
dc.identifier.hkuros187298
 
dc.identifier.isiWOS:000276672500019
 
dc.identifier.issn0194-911X
2013 Impact Factor: 7.632
2013 SCImago Journal Rankings: 3.702
 
dc.identifier.issue5
 
dc.identifier.pmid20231525
 
dc.identifier.scopuseid_2-s2.0-77951499390
 
dc.identifier.spage1165
 
dc.identifier.urihttp://hdl.handle.net/10722/135220
 
dc.identifier.volume55
 
dc.languageeng
 
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://hyper.ahajournals.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofHypertension
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAngiotensin II - pharmacology
 
dc.subject.meshHypertension - chemically induced - physiopathology
 
dc.subject.meshInflammation - prevention and control
 
dc.subject.meshSmad3 Protein - deficiency - genetics - physiology
 
dc.subject.meshVentricular Remodeling - drug effects - genetics - physiology
 
dc.subjectAngiotensin II
 
dc.subjectCardiac remodeling
 
dc.subjectHypertension
 
dc.subjectSmad3
 
dc.subjectTGF-β
 
dc.titleSmad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling
 
dc.typeArticle
 
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<contributor.author>Yang, F</contributor.author>
<contributor.author>Yue, W</contributor.author>
<contributor.author>Deng, C</contributor.author>
<contributor.author>Lau, CP</contributor.author>
<contributor.author>Tse, HF</contributor.author>
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<description.abstract>Although Smad3 is a key mediator of fibrosis, the functional role of Smad3 in hypertensive cardiovascular disease remains unclear. The present study tested the hypothesis that angiotensin II may activate the transforming growth factor-&#946;/Smad3 pathway to mediate hypertensive cardiac remodeling in Smad3 knockout (KO) and wild-type mice by subcutaneous angiotensin II infusion and in the primary culture of Smad3 KO cardiac fibroblasts. Fourteen days after angiotensin II infusion, both Smad3 KO and wild-type mice developed equal levels of high blood pressure. However, hypertensive cardiac fibrosis and inflammation were developed in Smad3 wild-type but not in Smad3 KO mice. This was demonstrated by the findings that mice lacking Smad3 were protected against a fall in left ventricular ejection fraction (P&lt;0.05), an increase in left ventricular mass (P&lt;0.05), and the development of cardiac fibrosis and inflammation, including upregulation of transforming growth factor-&#946;1, connective tissue growth factor, collagen I/III, &#945;-smooth muscle actin, interleukin 1&#946;, tumor necrosis factor-&#945;, monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and an increase in macrophage and T-cell infiltration in left ventricular tissues (all P&lt;0.01, respectively). Additional studies in vitro also revealed that angiotensin II-induced cardiac fibrosis and inflammation were prevented in Smad3 KO cardiac fibroblasts. Inactivation of both Smad3 and nuclear factor &#954;B/p65 signaling pathways was a key mechanism by which Smad3 KO mice were protected from angiotensin II-mediated hypertensive cardiac remodeling. In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease. Copyright &#169; 2010 American Heart Association. All rights reserved.</description.abstract>
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Author Affiliations
  1. National Institute of Diabetes and Digestive and Kidney Diseases
  2. The University of Hong Kong
  3. Chinese University of Hong Kong