Heme oxygenase-1-mediated protection: potential role of nonheme iron-nitric oxide complexes.

Role of Nonheme Iron–Nitric Oxide Complexes To the Editor: In a recent paper, Tulis and coworkers1 reported that transfectional overexpression of heme oxygenase-1 (HO-1) inhibits arterial remodeling after balloon angioplasty via a mechanism involving apoptosis. HO-1 is a stress response protein that degrades heme to carbon monoxide, biliverdin, and nonheme iron. In general, overexpression of HO-1 plays a cytoprotective role against a variety of oxidative stimuli. Interestingly, cells overexpressing HO-1 exhibit low levels of free iron because of the upregulation of ferritin and the extraction of iron into the extracellular space.2 The elimination of pro-oxidant iron from the cell is considered to be an important mechanism of HO-1– mediated protection against oxidative stress.2 How HO-1 overexpression stimulates apoptosis in the medial wall of injured artery is unclear. We believe that, among potential mechanisms of HO-1– mediated stimulation of apoptosis in injured vascular tissue, at least one may be related to nitric oxide (NO). Vascular injury is associated with the expression of inducible NO synthase (iNOS) leading to an overproduction of NO, which is known to stimulate apoptosis and inhibit neointima formation after balloon angioplasty.3 In nonvascular cells, the content of intracellular free nonheme iron plays an important role in protecting against NO apoptosis.4 The mechanism of this protection involves the interaction of NO and free iron leading to the formation of dinitrosyl iron complexes (DNIC), which in turn inhibit the key apoptotic enzyme, caspase.4 We hypothesize that in injured vascular tissue, iNOSdependent generation of DNIC may lead to the inhibition of caspase(s) and suppression of NO-dependent apoptosis, thus contributing to neointima formation. HO-1, via a decrease in intracellular nonheme iron content, may prevent caspase inhibition by DNIC and sensitize cells to apoptosis, thus attenuating neointima formation. If this hypothesis proves to be correct, the co-induction of both HO-1 and iNOS may have an additive effect in preventing arterial remodeling after balloon injury.