NITRIC-OXIDE AND ENDOTHELIN IN THE DEVELOPMENT OF CARDIAC ALLOGRAFT VASCULOPATHY - POTENTIAL TARGETS FOR THERAPEUTIC INTERVENTIONS

Extensive research has been carried out in recent years to discover th e potential risk factors contributing to cardiac allograft atherogenes is. Injury to endothelial cells has been regarded as an important earl y mechanism in the development of transplant atherosclerosis; it leads to the manifestation of epicardial and microvascular endothelial dysf unction and development of intimal hyperplasia. Moreover, continuous m inor endothelial cell damage contributes to endothelial dysfunction wh ich reflects one of the first measurable steps in the cascade of ather ogenesis without macroscopic evidence of vascular lesions. The discove ry of two important vasoactive substances nitric oxide (NO) and endoth elin (ET) has brought new insights but also new unsolved questions reg arding the mechanisms leading to atherosclerosis. To date it is known that both substances play a major role in both prevention and developm ent of atherosclerosis, NO appears to be protective in low concentrati ons by inhibiting leukocyte and platelet activation/adherence and smoo th muscle cell proliferation. Impaired endothelial NO production, as o ne cause of endothelial dysfunction may occur in early stages of ather osclerosis before macroscopic lesions are evident. In addition, increa sed endothelin release also results in endothelial dysfunction by indu cing vasoconstriction; it promotes vascular lesion formation due to en dothelial- and vascular smooth muscle cell proliferation. Direct and i ndirect manipulation of both the NO and ET signal transduction systems may provide novel preventive and therapeutic approaches for limiting transplant atherogenesis and to treat native atherosclerosis. This rev iew summarizes important experimental and clinical evidence which poin ts to nitric oxide and endothelin as potential therapeutic targets in the process of cardiac allograft vasculopathy. (C) 1998 Elsevier Scien ce Ireland Ltd. All rights reserved.