Nitric oxide, a janus-faced therapeutic target for diabetic microangiopathy-Friend or foe?

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathy, which could account for disabilities and high mortality rates in patients with diabetes. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic vascular complications have now become one of the most challenging health problems. Nitric oxide (NO) is a pleiotropic molecule critical to a number of physiological and pathological processes in humans. NO not only inhibits the inflammatory-proliferative reactions in vascular wall cells, but also exerts anti-thrombogenic and endothelial cell protective properties, all of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes. However, high amounts of NO produced by inducible NO synthase (iNOS) and/or peroxynitrite (ONOO(-)), a reactive intermediate of NO with superoxide anion are involved in pro-inflammatory reactions and tissue damage as well. This implies that NO is a janus-faced molecule and acts as a double-edged sword in vascular complications in diabetes. Further, NO is synthesized from l-arginine via the action of NO synthase (NOS), while NOS is blocked by endogenous l-arginine analogues such as asymmetric dimethylarginine (ADMA), a naturally occurring amino acid which is found in the plasma and various tissues. These findings suggest that amounts of NO locally produced, oxidative stress conditions and level of ADMA could determine the beneficial and detrimental effects of NO on vascular complications in diabetes. In this paper, we review the janus-faced aspects of NO in diabetic microangiopathy.