Juan Acosta | PubMed Health

PubMed2004

Complement and complement regulatory proteins as potential molecular targets for vascular diseases.

By-products of complement activation and complement regulatory proteins are increasingly recognized to play an important pathogenic role in a variety of vascular diseases including atherosclerosis, ischemia and reperfusion injury, hyperacute graft rejection, vasculitis, and the vascular complications of human diabetes. "Self" damage by autologous complement is mediated by activation products of the complement cascades or by direct insertion of the membrane attack complex (MAC) into cell membranes. Specifically, insertion of MAC complexes into endothelial cells results in the release of an array of growth factors and cytokines that induces proliferation, inflammation and thrombosis in the vascular wall. This paper reviews complement and complement regulatory proteins with specific focus on the vasculature and vascular diseases; it highlights complement and its regulators as potential targets for the rational design of mechanism-specific drugs for the treatment of some of the most prevalent human diseases.

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PubMed2004

Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes.

Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.

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