Circulating heavy chain IgG, a pathological mediator for coronary artery disease, recognizes platelet surface receptors of both prostacyclin and insulin

Abstract

Although an increased incidence of premature cardiovascular disease has been determined to be the major cause of mortality in subjects with chronic spinal cord injury the identity of the pathophysiological mediators of cardiovascular disease in spinal cord injury remains obscure. Because both insulin and prostacyclin could be important in the prevention of thrombosis, the status of insulin-induced nitric oxide production and the prostacyclin high-affinity receptor interaction in platelets in subjects with spinal cord injury was studied. It was established that the insulin-induced nitric oxide synthesis in platelets from spinal cord-injured subjects was markedly impaired (0.053-0.058, P=0.37-0.44) compared to (0.062-0.53 μM/10⁸ platelets, P<0.001) due to the presence of a free heavy chain IgG (M_r 47 kDa) in the circulation of subjects with spinal cord injury. This IgG not only blocked insulin receptor binding sites (without affecting dissociation constant of the hormone binding, K_d1= 2 × 10⁻⁹ M) for the synthesis of nitric oxide but also blocked the prostacyclin receptor interaction in normal platelets. Since the presence of circulating heavy chain of IgG could block the antithrombotic effect of both insulin and prostacyclin, the free heavy chain of the IgG molecule was thought to be one of the pathological mediators for the increased incidence of cardiovascular disease in individuals with spinal cord injury. The cross-reactivity of the free heavy chain with two different receptors antigens was thought to be related to the presence of several regions of homology in the amino acid sequence in the insulin and prostacyclin receptor molecules.