Summary

In the redox theory of HPV, we propose the existence of a mitochondrial redox sensor in complexes I and III that is linked to several 02-sensitive K+ channels (e.g., Kv1.5) by diffusible redox mediators (e.g., H202). In hypoxia, a rapid and dynamic alteration in levels of AOS will reduce critical amino acids in certain Kv channels which would translate into a conformational change ofthe channel, decreasing its open probability. The resultant Em depolarization increases intracellular Ca2+by promoting Ca2+ influx. This increased Ca2+would act on the actin-myosin apparatus thus precipitating HPV (Fig. 10).

One of the more viable alternatives to the mitochondrial origins of AOS is that a similar signal is derived from membrane-bound NADPH oxidase. The NADPH oxidase system is a multisubunit assembly consisting of a membrane-

Figure 9: Redox control of PA tone. A: The sulfhydryl oxidant, diamide, reverses HPV in anesthetized dogs. Preincubation of diamide with reduced glutathione prevents this effect. B: Endothelium-denuded PA rings constrict in response to the electron shuttling agent duroquinone and this is reversed by diamide (Reproduced from Ref. 99 with permission).

bound catalytic complex of the 91 kDa subunit of cytochrome oxidase (gp91phox) and p22phox, which altogether forms a flavo-cytochrome b558. The cytosolic regulatory component consists ofp47phox, p67phox and other regulatory subunits such as the GTPase proteins Rac-1 or Rac-2 (49). Studies in neutrophils have shown that electrons derived from NADPH are shuttled to 02 by the oxidase at a rapid rate during normoxia generating 02". This 02" is converted to H202 via SOD. The H202 mediator induces a site-specific oxidation ofcytosolic regulatory proteins (41). Because of its role in AOS generation, initially, it was believed that NADPH oxidase regulates 02 sensing in various systems such as the carotid body, neuroepithelial bodies and pulmonary vasculature (49). However, subsequent studies proved otherwise especially in patients suffering from chronic granulomatous disease (CGD). CGD is a genetic defect in one or more of the subunits ofNADPH oxidase and presents as a broad spectrum infection of organ systems with abscess formation. Although NADPH oxidase system is disrupted, patients with CGD are still able to maintain HPV (128). Furthermore, mice-deficient in NADPH oxidase activity by mutation of the X-linked gp91phox, showed that HPV was unaltered. In addition, studies with rotenone constriction also showed that hypoxic response was preserved in these NADPH oxidase-deficient mice. Thus, this form of NADPH oxidase does not contribute to HPV (15). However, it remains possible that a form of NADPH oxidase called novel oxidase (NOX) may have a role.

Figure 10: Alternative sources of AOS for the proposed redox mechanism for HPV. The redox theory of HPV suggests that AOS are produced in proportion to Po2 by 02 sensors, likely complexes I and III of the mitochondrial ETC, and possibly also cytochrome-based vascular oxidases. The changes in AOS production alter the gating and open probability of the effectors of HPV, the 02-and redox-sensitive Kv channels such as Kv1.5 and Kv2.1.

Figure 10: Alternative sources of AOS for the proposed redox mechanism for HPV. The redox theory of HPV suggests that AOS are produced in proportion to Po2 by 02 sensors, likely complexes I and III of the mitochondrial ETC, and possibly also cytochrome-based vascular oxidases. The changes in AOS production alter the gating and open probability of the effectors of HPV, the 02-and redox-sensitive Kv channels such as Kv1.5 and Kv2.1.

Vascular SMCs also contain gp91phox homologs, called NOX, which preferentially utilize NADPH versus NADH as substrate. NOXs are also inhibited by DPI and are potentially important sources of AOS production in systemic vascular SMCs (52). However, most studies of NOX have been performed in systemic arteries and have measured AOS production in response to vasoconstrictors (e.g., angiotensin II) or mitogens (e.g., PDGF). There is little evidence that NOX are involved in PASMC AOS production or HPV, since little AOS signal remains in the NADPH oxidase gp91phox knockout mice. It is also noteworthy that angiotensin II does not cause an acute change in AOS production in mouse lungs at doses that cause vasoconstriction (14, 15). Perhaps the predominant source of AOS differs between Pas (where AOS may be signaling molecules serving to optimize 02 uptake from the environment) and systemic arteries (where AOS may be involved in the pathogenesis of atherosclerosis and systemic hypertension).

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