Journal
CARDIOVASCULAR RESEARCH
Volume 100, Issue 2, Pages 211-221Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvt181
Keywords
Cardiac fibrosis; eNOS inhibition; Fibrocytes; SDF-1
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Funding
- Deutsche Forschungsgemeinschaft [KFO 196, LA997/6-1]
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The endothelial nitric oxide synthase (eNOS) contributes to cardiac remodelling. We studied the role of eNOS in the development of myocardial fibrosis during cardiac overload. Ten-week-old male C57/Bl6 wildtype (WT) and eNOS mice (eNOS(/)) were subjected to transverse aortic constriction (TAC, 360 m) and WT were treated with l-N-G-nitroarginine methyl ester (l-NAME, 100 mg/kg/day) for 35 days. Inhibition of eNOS by l-NAME induced interstitial fibrosis, augmented replacement fibrosis, and induced apoptosis of cardiac fibroblasts and cardiomyocytes. l-NAME and eNOS(/) markedly increased the fibrosis induced by TAC and enhanced the myocardial prevalence of CXCR4(pos) fibroblasts. Myocardial stromal-derived factor-1 (SDF-1) expression was up-regulated by l-NAME and down-regulated after TAC. Blood pressure lowering by co-treatment with hydralazine (250 mg/L/day) did not reverse the l-NAME effects. In mice transplanted with green fluorescent protein (GFP)(pos) bone marrow, l-NAME increased the percentage of GFP(pos) fibroblasts in the myocardium to 4570. Strain-mismatched BMT of eNOS(/)-BM increased and of WT-BM decreased the percentage of CXCR4(pos) fibroblasts in all groups. The number of fibrocytes (CD45(pos) collagen I-pos cells) in the peripheral blood and in the bone marrow was increased both by TAC and l-NAME. l-NAME but not the inhibitor of inducible NOS 1400 W and of neuronal NOS 7-nitroindazole increased hydroxyproline and collagen I1. l-NAME up-regulated SDF-1 mRNA in cultured neonatal rat cardiac fibroblasts as well as their migratory capacity. eNOS inhibition induces and enhances cardiac fibrosis independently of blood pressure by activating SDF-1/CXCR4, extracellular matrix production in cardiac fibroblasts and by increasing recruitment of fibrocytes from the bone marrow.
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