Inhibition of HIF-1alpha activity by BP-1 ameliorates adjuvant induced arthritis in rats.
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.
Shankar
J
J
Department of Microbiology & Immunology, University of Illinois at Chicago, Chicago, USA.
Thippegowda
P B
PB
Kanum
S A
SA
D000081:Acetamides / Q000737:chemistry / Q000627:therapeutic use*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
C523255:2-benzoyl-phenoxy acetamide; D000081:Acetamides; D018501:Antirheumatic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat