Circulation Research. 2004
Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117070.86556.9F
Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117070.86556.9F
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Submitted on August 27, 2003
Revised on December 18, 2003
Accepted on December 22, 2003
B-Type Natriuretic Peptide Exerts Broad Functional Opposition to Transforming Growth Factor-
in Primary Human Cardiac Fibroblasts. Fibrosis, Myofibroblast Conversion, Proliferation, and Inflammation
Ann M. Kapoun ;
From Scios Inc, Fremont, Calif.
* To whom correspondence should be addressed. E-mail: protter{at}sciosinc.com.
The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-
(TGF-) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF--induced effects on primary human cardiac fibroblasts. BNP inhibited TGF--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- and BNP for 24 and 48 hours. TGF- but not BNP treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF- effects; 88% and 85% of all TGF--regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF--regulated genes related to fibrosis (Collagen 1, fibronectin, CTGF, PAI-1, and TIMP3), myofibroblast conversion (
-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation (PDGFA, IGF1, FGF18, and IGFBP10), and inflammation (COX2, IL6, TNF-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--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.
Key words: B-type natriuretic peptide • transforming growth factor-
•
cardiac fibroblasts •
fibrosis
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