Adverse Biventricular Remodeling in Isolated Right Ventricular Hypertension Is Mediated by Increased Transforming Growth Factor-beta 1 Signaling and Is Abrogated by Angiotensin Receptor Blockade

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Arquivos
art_ASSAD_Adverse_Biventricular_Remodeling_in_Isolated_Right_Ventricular_Hypertension_2013.PDF (2.09 MB)
Citações na Scopus
72
Tipo de produção
article
Data de publicação
2013
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
AMER THORACIC SOC
Autores
FRIEDBERG, Mark K.
CHO, Mi-Young
LI, Jing
SUN, Mei
ROHAILLA, Sagar
HONJO, Osami
APITZ, Christian
REDINGTON, Andrew N.
Citação
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, v.49, n.6, p.1019-1028, 2013
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
The pressure-loaded right ventricle (RV) adversely affects left ventricular (LV) function. We recently found that these ventricular-ventricular interactions lead to LV myocardial fibrosis through transforming growth factor-beta 1 (TGF-beta 1) signaling. We investigated the mechanisms mediating biventricular fibrosis in RV afterload and their potential modification by angiotensin receptor blockade. An adjustable pulmonary artery band (PAB) was placed in rabbits. In sham-operated control rabbits, the band was left uninflated (n = 6). In the RV afterload group, the PAB was sequentially inflated to generate systemic RV pressure at 28 days (n = 8). In a third group, the PAB was inflated to systemic levels, and the angiotensin receptor blocker losartan was added (n = 6). Five weeks after surgery, the animals were killed for assessments of biventricular hypertrophy, fibrosis, apoptosis, and the components of their signaling pathways. PAB animals developed biventricular hypertrophy, fibrosis, and apoptosis, versus sham rabbits, in which these conditions were decreased with losartan. RV and LV TGF-beta 1, connective tissue growth factor (CTGF) (CCN2), endothelin-1 (ET-1), endothelin receptor B, and matrix metalloproteinase 2/9 mRNA levels were increased in PAB animals versus sham animals, and decreased with losartan. Given the marked biventricular CTGF up-regulation in PAB and down-regulation with losartan, we investigated CTGF signaling. RV and LV Smad 2/3/4 protein levels and LV RhoA mRNA levels were increased with PAB and reduced with losartan. In conclusion, isolated RV afterload induces biventricular fibrosis and apoptosis, which are reduced by angiotensin receptor blockade. Adverse ventricular-ventricular interactions induced by isolated RV afterload appear to be mediated through TGF-beta 1-CTGF and ET-1 pathways.
Palavras-chave
right ventricular afterload, ventricular-ventricular interactions, apoptosis, angiotensin receptor blocker
URI
https://observatorio.fm.usp.br/handle/OPI/4493
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Coleções
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - LIM/11
Artigos e Materiais de Revistas Científicas - ODS/03