Myeloperoxidase-mediated lipoprotein carbamylation as a mechanistic pathway for atherosclerotic vascular disease.
There is an emerging and significant body of research that suggests that MPO (myeloperoxidase) may be a critical mediator in dysfunctional lipoprotein formation and, hence, atherogenic initiation and progression. MPO is a haem peroxidase found in leucocytes and is abundant in macrophages surrounding atherosclerotic lesions. Several lines of evidence support the role of MPO-mediated carbamylation of proteins in atherogenesis. The generic mechanism of MPO-mediated protein carbamylation has been elucidated recently and has been identified as a potentially crucial pathway that links smoking, inflammation and atherogenesis. HDL (high-density lipoprotein) exerts a physiologically beneficial effect of reducing arterial cholesterol deposition; however, there are considerable gaps in current understanding of the molecular basis of dysfunctional HDL formation. Especially deserving of attention is a contextual understanding of dysfunctional pro-atherogenic HDL formation in light of inflammatory changes in atheroma. The present review is especially timely in light of the solved structures of nascent and discoidal HDL and integrates the biochemical significance of MPO carbamylation in the context of these structures. Various avenues of experimental investigation are explored which will be crucial in understanding the vascular consequences of dysfunctional HDL formation and the identification of novel mechanistic pathways in vascular disease. It is anticipated that further knowledge on the intricacies of dysfunctional HDL formation, potentially by an MPO-driven pathway, will lead to considerable progress in identifying novel drug targets for atherosclerosis and characterization of the primary atherogenic process.
Sirpal
Sanjeev
S
University of Miami School of Medicine, Miami, FL 33101, USA. ssirpal@med.miami.edu