Figure 4
Proposed mechanism for organic nitrate bioactivation, induction of oxidative stress and protective effects. Highly potent organic nitrate (tri- and tetranitrates) are bioactivated by mitochondrial ALDH. The bioactivation (reduction cycle) requires two thiol groups at the active site of the enzyme which are oxidized to the disulfide during the conversion which yields the denitrated metabolite and an NOx species that is similar to NO. Enzymatic activity is restored by reduced lipoic acid/lipoamide which is recycled by lipoamide reductase (LAR), thioredoxin/thioredoxin reductase system (Trx/TrxR) or glutathione/glutathionereductase system (GSH/GR). GTN leads to mechanism-based inactivation of the enzyme but also triggers mitochondrial oxidative stress which may directly inactivate mtALDH, deplete dihydrolipoic acid or interfere with its reductases. In contrast, PETN induces HO-1 which by breakdown of porphyrins yields the potent antioxidant bilirubin, the anti-inflammatory compound CO and induces ferritin, another protective enzyme which decreases free iron and prevents Fenton-type reactions.