Heme Oxygenase-1 Induction and Organic Nitrate Therapy: Beneficial Effects on Endothelial Dysfunction, Nitrate Tolerance, and Vascular Oxidative Stress

Figure 3

Scheme illustrating the mechanisms underlying the oxidative stress concept of nitrate tolerance in response to GTN treatment and the mechanisms underlying the beneficial vascular effects in response to PETN. PETN and GTN are bioactivated by mitochondrial ALDH (ALDH-2) yielding 1,2-glyceryl dinitrate and PETriN, respectively, as well as a yet undefined nitrogen species (NO_x, probably nitrite) that undergoes further reduction by the mitochondrial respiratory chain or acidic disproportionation to form an activator of sGC (probably nitrico xide). GTN treatment induces mitochondrial reactive oxygen and nitrogen species formation (ROS/RNS). These ROS/RNS in turn inhibit the GTN bioactivation process by inactivation of ALDH-2 or by inhibiting the repair system of the ALDH-2, which includes lipoic acid, as well as a reductase system depending on the NADH or NADPH (lipoicacid reductase (LAR), thioredoxin/thioredoxin reductase (Trx/TrxR) or glutathione/glutathione reductase (GSH/GR). In contrast to GTN, PETN provides potent antioxidative effects by inducing HO-1 and ferritin, which in turn decrease ROS levels and therefore protect the ALDH-2 from ROS mediated inactivation. Adapted from [31].