Since BH4 levels are directly linked to eNOS activity and endothelial function [44, 45] and GCH-1 is oxidatively degraded by activation of the proteasome26S [46], activation of antioxidant pathways by induction of HO-1 may represent an attractive explanation for the tolerance and endothelial dysfunction devoid profile of chronic PETN therapy and the undesired side effects of most other organic nitrates (but most pronounced for GTN treatment). The gene discussed is HMOX1; the disease is endothelial dysfunction.