Shankar J, Thippegowda P B, Kanum S A
Department of Microbiology & Immunology, University of Illinois at Chicago, Chicago, USA.
Biochem Biophys Res Commun. 2009 Sep 18;387(2):223-8. doi: 10.1016/j.bbrc.2009.01.086.
Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1alpha (HIF-1alpha), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1alpha. BP-1 administered hypoxic endothelial cells and arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1alpha, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.
类风湿性关节炎（RA）是一种慢性炎症性血管生成疾病。炎症性滑膜炎是RA的一个标志，其本质上是缺氧的。血管内皮生长因子（VEGF）是血管生成的关键调节因子之一，在RA的发病机制中过度表达。VEGF的表达受缺氧诱导因子-1α（HIF-1α）调节，HIF-1α是体内稳态的主要调节因子，在缺氧诱导的血管生成中起关键作用。在本研究中，我们表明合成二苯甲酮类似物2-苯甲酰苯氧基乙酰胺（BP-1）可通过靶向VEGF和HIF-1α，在实验性佐剂诱导性关节炎（AIA）大鼠模型中作为一种新型抗关节炎药物。给予BP-1的缺氧内皮细胞和关节炎动物明显显示VEGF表达下调。此外，BP-1抑制HIF-1α的核转位，进而抑制VEGF基因的转录。这些结果表明BP-1衍生物作为抗关节炎药物与传统化疗药物联合应用可能具有进一步的临床应用前景。
