Abstract 18637: Cardiac Fibroblasts Negatively Regulate Angiogenesis Through Their Secreted Novel Anti-angiogenic Factor in vitro and in vivo

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Introduction: Angiogenesis is strictly regulated by mechanisms between promotion and inhibition. Although angiogenesis promoting mechanisms have been well studied in ischemic heart diseases, angiogenesis inhibitory mechanisms have not been well elucidated. Recently we have identified a novel anti-angiogenic factor X derived from human cardiac fibroblasts (cFB), which suppress endothelial cell network formation in co-culture. However the properties of factor X including influence of aging and ischemic condition on the expression of factor X are not fully elucidated.

Methods and Results: When we evaluated mRNA expression of factor X in various rat organs by quantitative RT-PCR analysis, factor X was dominantly expressed in heart and brain. Immunohistochemial analysis revealed that factor X was specifically observed in the interstitial tissues of heart. Next we isolated fibroblasts from heart or dermal tissues in neonatal (2day) and adult (8W) rats and those fibroblasts were co-cultured with neonatal rat heart-derived CD31(+) endothelial cells (n=4, p<0.05). Consistent with remarkable higher mRNA expression of factor X in cFB compared with dermal fibroblasts (dFB) in both ages (n=4, p=0.005 and p=0.007), significant inhibition of endothelial cell network formation was observed in cFB in comparison with dFB. Finally we generated myocardial infarction (MI) model by the permanent ligation of left anterior descending artery of adult rats and evaluated mRNA expression of factor X in hearts. Factor X was significantly downregulated at day1 after MI (n=4, p=0.015), but not at day4 and day8 (n=4, p>0.05). These finding suggest that angiogenesis inhibitory mechanisms might not be sufficiently suppressed to promote angiogenesis in ischemic heart diseases.

Conclusions: cFB express a novel anti-angiogenesis factor in nature and the expression of factor X might be still maintained in ischemic heart diseases. Understanding of regulatory mechanisms of factor X-mediated angiogenesis inhibition and the development of strategy to inhibit factor X expression or function might provide us the novel angiogenic therapy for ischemic heart diseases.

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