GCH1 and endothelial dysfunction: We [39], [40], [41] and others [42] have shown that the UPS can contribute to the development of endothelial dysfunction, which is reflected as enhanced 26S proteasome activity, an accelerated degradation of endothelial-protective molecules (such as the guanosine 5-triphosphate cyclohydrolase I or GTPCH I, the rate limiting enzyme essential for the de novo synthesis of an eNOS co-factor [39], [40], [43]), and consequent impaired endothelium-dependent vasorelaxation.