Oxidant-redox regulation of pulmonary vascular responses to hypoxia and nitric oxide-cGMP signaling

Abstract

Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide. HPV results from hypoxia removing vasodilation by peroxide. Decreased superoxide generation by Nox4 oxidase and its conversion to peroxide by Cu,Zn-SOD appear to be potential factors in sensing hypoxia, and decreased cGMP-associated vasodilation and removal of redox controlled vasodilator mechanisms by increased cytosolic NADPH may be key coordinators of the HPV response. Oxidant generation associated with vascular disease processes, including the removal of NO by superoxide, and attenuation of its ability to stimulate cGMP production by oxidation of the heme and thiols of soluble guanylate cyclase attenuate potential beneficial actions of NO on pulmonary arterial function. While pulmonary hypertension appears to have multiple poorly understood effects on redox-associated processes, potentially influencing responses to hypoxia and NO-cGMP signaling, much remains to be elucidated regarding how these processes may be important factors in the progression, expression and therapeutic treatment of pulmonary hypertension.

Fig. 1

Model showing how hypoxia is hypothesized to elicit a hypoxic pulmonary vasoconstriction (HPV) response seen in bovine pulmonary arteries by removal of a relaxation by hydrogen peroxide which appears to be derived from Nox4 oxidase. The model shows how hypoxia decreases the generation of superoxide (O₂^.−) by Nox4 oxidase needed for conversion to hydrogen peroxide by Cu,Zn-SOD and mechanisms through which peroxide can maintain a relaxation under normoxic conditions potentially mediated through stimulation of cGMP-dependent protein kinase (PKG) activity. In addition, by hypoxia decreasing cytosolic NADPH consumption for the generation and metabolism of peroxide, it may also reverse relaxing mechanisms controlled by cytosolic NADPH oxidation and oxidized glutathione (GSSG) formation. In this model, the relaxing mechanisms removed by hypoxia may involve decreasing intracellular calcium [Ca²⁺]_I (e.g. through increased uptake by the SERCA pump and decreased Ca²⁺ influx) and suppressing the action of Ca²⁺ on the contractile apparatus through inhibiting Rho kinase activity.

Fig. 2

Model showing how multiple oxidant mechanisms potentially associated with the progression of vascular disease processes can attenuate endogenous nitric oxide (NO) vasodilation mediated through stimulation of cGMP production by soluble guanylate cyclase (sGC), and how new therapies being developed for the to treat pulmonary hypertension potentially function through restoring cGMP-mediated relaxation. Oxidant processes associated with the formation of reactive oxygen species (ROS), peroxynitrite (ONOO) and oxidized glutathione (GSSG), etc. can inhibit NO-mediated increases in cGMP by superoxide (O₂^.−) directly oxidizing NO to ONOO, and by attenuating the ability of sGC to be activated by NO through oxidation of iron (Fe) of heme and thiol sites (SH) on sGC. The model also shows the potential importance of how the regulation of cytosolic NADPH generation by glucose-6-phopshate dehydrogenase (G6PD) reaction potentially functions at multiple sites to reverse the effects of heme and thiol oxidation, and how therapeutically beneficial drugs inhibiting removal of cGMP by phosphodiesterases (PDE, e.g. Sildenafil) function to reverse pulmonary hypertension.