The present invention is based in part on the discovery that the upstream
open reading frame (uORF) in the extended 5'-untranslated region (5'-UTR)
argininosuccinate synthase (AS) mRNA species is functional, and when
functional, limits overall AS expression as well as nitric oxide (NO)
production. Thus, the extended 5'-UTR AS mRNA species is a mechanism for
regulating AS expression and NO production, and provides a target for the
treatment of pathophysiological conditions associated with vascular
endothelial dysfunction and characterized by impairment of NO production,
such as heart failure, hypertension, hypercholesterolemia,
atherosclerosis, and diabetes.