Sangha, Jason (2011)
M.Phil. thesis, University of Birmingham.
Restricted to Repository staff only until July 2015.
Biliverdin Reductase (BVR) functions downstream of Heme Oxygenase 1 (HO-1) in the process of heme degradation and catalyses the reduction of biliverdin to bilirubin. For over thirty years, BVR was regarded as rather a trivial enzyme whose only known function was to aid heme disposal. Over the last decade however, it has become increasingly clear that BVR is pleiotropic in function and for example, functions as a dual-specificity protein kinase and also as a transcription factor. The bile pigment bilirubin is now known to possess potent anti-inflammatory and antioxidant effects, and this finding is underscored clinically by the observation that mild hyperbilirubinemia, due to Gilbert’s syndrome, protects patients against cardiovascular diseases associated with atherosclerosis. However a number of studies have suggested that BVR, aside from its bilirubin generating capacity, is pro-inflammatory. In the present study, we show that BVR acts in an anti-inflammatory manner in the endothelium; by increasing eNOS activation and nitric oxide release, inducing HO-1 protein expression and by inhibiting TNFα-induced leukocyte-endothelium interaction. These highly novel findings give credence to future therapeutic strategies aiming to modulate BVR activity in vivo in the fight against chronic inflammatory diseases such as atherosclerosis.
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