Increase of metabolic activity and disruption of normal contractile protein distribution by bilirubin oxidation products in vascular smooth-muscle cells

Abstract

The authors concluded that BOXes, OA, and PMA alter VSMC morphology and metabolic activity, events that have been observed during vascular remodeling. Although the mechanism remains unclear, the results indicate that BOXes may play a role in the vascular remodeling that occurs following aneurysmal SAH.

Bilirubin oxidation products (BOXes): synthesis, stability and chemical characteristics

“…More recently, bilirubin oxidation has started to gain interest and attention [15][16][17][18]38,45,46,51]. What is lacking, however, is an understanding of the resultant species and the biological importance of the compounds made post oxidation of bilirubin [3,25,36,38]. Our previous studies and the data presented here suggest that oxidized bilirubin may be an important and novel molecular species in biological systems.…”

“…BOXes have been reported to be involved in the disease sequelae of subarachnoid haemorrhage induced cerebral vasospasm [3,4,22,25,36,38]. They were proposed to be produced by the oxidation of bilirubin in the subarachnoid haemorrhage patient and cause or contribute to vasospasm in those patients because they were present in the spinal fluid obtained from these patients [38] and caused vasospasm like events in model systems [3,4,22,25,36,38].…”

“…They were proposed to be produced by the oxidation of bilirubin in the subarachnoid haemorrhage patient and cause or contribute to vasospasm in those patients because they were present in the spinal fluid obtained from these patients [38] and caused vasospasm like events in model systems [3,4,22,25,36,38]. Since they were first described by Kranc et al [22] the focus of BOXes studies has been on the pathology and physiology of BOXes, with less focus on the chemical characteristics of BOXes.…”

“…It is relatively stable with a planar configuration containing a hinge between the 2 and 3 pyrroles. BOXes are also relatively planar and are likely to be able to cross membranes and appear to have numerous biological effects [3,22,25,38]. Nonetheless, to date, there have been no definitive binding or specific uptake studies on BOXes and target molecules/cells.…”

“…The oxidation of (unconjugated) bilirubin has largely focused on the degradation of bilirubin between the pyrroles [5], with little discussion concerning the putative biological activity of the products of bilirubin oxidation [49]. We recently reported on a new family of bilirubin oxidation products found following subarachnoid hemorrhage [3,22,25,38]. It appears that bilirubin oxidation products (BOXes) can be formed by the direct, nonenzymatic oxidation of bilirubin with hydrogen peroxide [22].…”