Pharmacological targeting of endothelial nitric oxide synthase dysfunction and nitric oxide replacement therapy.

The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life-years lost. Endothelial dysfunction is a pathomechanism associated with these risk factors and stressors, and is an early predictor of atherosclerosis. Oxidative stress triggers endothelial dysfunction, a hallmark of cardiovascular diseases. Endothelial dysfunction is largely based on impaired endothelial nitric oxide synthase (eNOS) function and activity or down-stream signalling of nitric oxide. Molecules affecting eNOS functionality, eNOS protein itself as well as components of the eNOS down-stream signalling cascade are attractive therapeutic targets for vascular integrity and homeostasis. Potential strategies for the pharmacological exploitation of these targets are highlighted in the present work. Recent advances and future therapeutic strategies for the treatment of cardiovascular and other diseases should be directed against such targets, including targets so far not considered sufficiently as well as lifestyle changes.