The role of inducible nitric oxide synthase in cardiac allograft rejection

Time for primary review 29 days. Cardiac transplantation is an effective therapy for end-stage heart failure with one and five year survival rates about 80% and 65% respectively [1]. Despite these good results, cardiac allograft rejection remains a problem which produces impaired ventricular performance and death of cardiac myocytes ultimately causing congestive heart failure, low cardiac output, hypotension and reduced pressor responses to catecholamines. Chronic allograft rejection also results in the development of transplant-associated coronary atherosclerosis, a vasculopathy that produces myocardial ischemia, infarction and sudden death and is the leading cause of death in cardiac transplant recipients after the first year [2]. Although there is a large body of evidence concerning the immunological interactions involved in cardiac allograft rejection, knowledge concerning the cellular and biochemical mechanisms responsible for contractile dysfunction and for death of heart muscle cells remains incomplete. Since an inflammatory reaction in the myocardium is an intrinsic component of the pathological changes observed during cardiac allograft rejection, our laboratory undertook an investigation of the participation of nitric oxide synthases, particularly the inducible nitric oxide synthase (iNOS), in the manifestations of cardiac allograft rejection. The five electron oxidation of l-arginine to l-citrulline and biologically active nitric oxide (NO) is important to a large variety of physiological and pathological processes [3, 4]. NO synthesis is accomplished by the three isoforms of NOS, the neuronal NOS (nNOS, NOS 1) originally identified in brain, inducible NOS (iNOS, NOS 2) originally identified in macrophages and endothelial NOS (eNOS, NOS 3) originally identified in endothelial cells. Constitutive nitric oxide synthases (nNOS and eNOS) require calcium and calmodulin as cofactors and generate low amounts of NO. Small amounts of NO released by endothelial cells in response to hormones or sheer stress interact with soluble guanylyl cyclases to increase the formation … * Corresponding author. Department of Medicine, Division of Cardiology, Columbia University, 630 West 168th Street, New York, NY 10032, USA. Tel.: +1 (212) 305-9052; Fax: +1 (212) 305-4648.