In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 94, No. 4 ( 2004-03-05), p. 453-461
Abstract:
The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-β (TGF-β) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-β–induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-β–induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis. cDNA microarray analysis was performed on RNA from cardiac fibroblasts incubated in the presence or absence of TGF-β and BNP for 24 and 48 hours. TGF-β, but not BNP, treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF-β effects; 88% and 85% of all TGF-β–regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF-β–regulated genes related to fibrosis ( collagen 1 , fibronectin , CTGF , PAI-1 , and TIMP3 ), myofibroblast conversion (α-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation ( PDGFA , IGF1 , FGF18 , and IGFBP10 ), and inflammation ( COX2 , IL6 , TNF α- induced protein 6 , and TNF superfamily , member 4 ). Lastly, BNP stimulated the extracellular signal-related kinase pathway via cyclic guanosine monophosphate–dependent protein kinase signaling, and two mitogen-activated protein kinase kinase inhibitors, U0126 and PD98059, reversed BNP inhibition of TGF-β–induced collagen-1 expression. These findings demonstrate that BNP has a direct effect on cardiac fibroblasts to inhibit fibrotic responses via extracellular signal-related kinase signaling, suggesting that BNP functions as an antifibrotic factor in the heart to prevent cardiac remodeling in pathological conditions.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/01.RES.0000117070.86556.9F
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2004
detail.hit.zdb_id:
1467838-X
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