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Symposium Reports |
1 Department of Pediatrics, Division of Neonatology, North-western University, Chicago, IL 60611, USA
Abstract
Hypoxic pulmonary vasoconstriction (HPV) becomes activated in response to alveolar hypoxia and, although the characteristics of HPV have been well described, the underlying mechanism of O2 sensing which initiates the HPV response has not been fully established. Mitochondria have long been considered as a putative site of oxygen sensing because they consume O2 and therefore represent the intracellular site with the lowest oxygen tension. However, two opposing theories have emerged regarding mitochondria-dependent O2 sensing during hypoxia. One model suggests that there is a decrease in mitochondrial reactive oxygen species (ROS) levels during the transition from normoxia to hypoxia, resulting in the shift in cytosolic redox to a more reduced state. An alternative model proposes that hypoxia paradoxically increases mitochondrial ROS signalling in pulmonary arterial smooth muscle. Experimental resolution of the question of whether the mitochondrial ROS levels increase or decrease during hypoxia has been problematic owing to the technical limitations of the tools used to assess oxidant stress as well as the pharmacological agents used to inhibit the mitochondrial electron transport chain. However, recent developments in genetic techniques and redox-sensitive probes may allow us eventually to reach a consensus concerning the O2 sensing mechanism underlying HPV.
(Received 30 October 2007;
accepted after revision 9 November 2007; first published online 9 November 2007)
Corresponding author P. T. Schumacker: Department of Pediatrics, North-western University, Ward Building 12–191, 303 East Chicago Avenue, Chicago, IL 60611, USA. Email: p-schumacker{at}northwestern.edu
Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to low alveolar oxygen tension and, in cases where a small percentage of the lung alveoli are hypoxic, HPV improves lung gas exchange by redistributing blood flow away from those areas toward regions with better oxygenation. Since its discovery in 1946 (von Euler & Liljestrand, 1946), the central question in the field of HPV has related to the underlying mechanism of O2 sensing. Over the years, a number of theories have been offered to explain how O2 is sensed, but some of these have not been pursued and others have not withstood more critical examination. Mitochondria have long been considered as a putative site of oxygen sensing because they consume O2 and therefore represent the intracellular site with the lowest oxygen tension. However, two opposing models have been proposed to explain how O2 is sensed during HPV. One model proposes that signalling by mitochondrial reactive oxygen species (ROS) decreases during hypoxia, while the other proposes that mitochondrial ROS signalling paradoxically increases. This continuing debate surrounding whether ROS signalling increases or decreases during hypoxia was the subject of a recent set of point/counter-point articles, and the reader is directed to those for a more detailed discussion of the debate (Ward, 2006; Weir & Archer, 2006).
Evidence implicating a decrease in ROS signalling during HPV
The theory that hypoxia decreases oxidant levels is based on early measurements using lucigenin or luminol chemiluminescence in perfused lungs, as well as measurements using chemiluminescence, Amplex Red, and 2',7'-dichlorofluorescin diacetate (DCF) fluorescence in endothelium-denuded rings of distal pulmonary artery (Archer et al. 1989, 1993; Mohazzab & Wolin, 1994; Michelakis et al. 2002). These findings suggest that a tonic level of ROS generation occurs during normoxia, which decreases during hypoxia owing to the lessened availability of the substrate, molecular O2. The mitochondria were suggested as the source of constitutive ROS production based on the findings that the mitochondrial inhibitors mimicked the hypoxic response, presumably by decreasing tonic mitochondrial ROS generation occurring through electron leak from the mitochondrial complexes to molecular O2 during normoxia (Archer et al. 1993; Archer & Michelakis, 2002). This led to the proposal that hypoxia decreases mitochondrial electron transport, thus decreasing ROS production by complex I and/or complex III while increasing cytosolic [NAD(P)H] (Archer et al. 1993; Michelakis et al. 2002). The decrease in NADH utilization by mitochondria could shift the cytosolic redox balance to a more reduced state, therefore increasing the [NADH]/[NAD+] ratio and the glutathione pool ratio ([reduced glutathione (GSH)]/[Oxidized glutathione (GSSG)]; Weir & Archer, 1995). This redox shift has been postulated to cause an inhibition of membrane K+ current via its effects on redox-sensitive voltage-gated potassium channel subunits. The resulting inhibition of membrane K+ current causes membrane depolarization, leading to the opening of L-type, voltage-gated Ca2+ channels and subsequent myocyte contraction. In support of this hypothesis, oxidizing agents caused vasodilatation in the isolated perfused lung (Weir et al. 1985), while reducing agents caused decreases in K+ currents in pulmonary artery smooth muscle cells (Reeve et al. 1995, 2001a,b; Olschewski et al. 2002, 2004; Weir et al. 2002).
Evidence implicating an increase in ROS signalling during HPV
An alternative to the hypoxia-induced decrease in ROS signalling was initially suggested by Marshall and co-workers, who argued that hypoxia activates an NAD(P)H oxidase, thereby signalling hypoxia with an increase in ROS production as measured by chemiluminescence in isolated pulmonary arterial smooth muscle cells (PASMC; Marshall et al. 1996). Other studies then followed, suggesting that acute hypoxia triggers an increase in ROS signalling in PASMC, as evidenced by an increase in oxidation of the intracellular probe 2',7'-dichlorofluorescin-diacetate (DCFH; Killilea et al. 2000; Waypa et al. 2001; Liu et al. 2003; Wang et al. 2007). In addition, further evidence of increasing ROS production during acute hypoxia was measured using lucigenin-derived chemiluminescence and suggested by electron paramagnetic resonance spectrometry, though the latter results did not achieve significance (Liu et al. 2003). In support of these findings, exogenous oxidants mimicked HPV, while the administration of antioxidants attenuated the HPV response (Waypa et al. 2001, 2002, 2006; Wang et al. 2007). Once again, the mitochondria were suggested as the source of the ROS signal; however, rather than decreasing the signal due to a decrease in substrate, mitochondrial ROS signalling was determined to increase paradoxically during hypoxia (Waypa et al. 2001, 2002, 2006; Wang et al. 2007). The resultant increase in ROS signalling during hypoxia is thought to initiate pulmonary arterial vasoconstriction through the release of Ca2+ from the sarcoplasmic reticulum (SR; Dipp & Evans, 2001; Dipp et al. 2001; Morio & McMurtry, 2002) via ryanodine receptors, which contain redox-sensitive cysteine thiols (Eu et al. 1999). Alternatively, SR Ca2+ release may occur through stimulation of ryanodine receptors via generation of the Ca2+-mobilizing β-NAD+ metabolite, cyclic ADP-ribose (cADPR; Dipp & Evans, 2001; Evans & Dipp, 2002), which is the result of an increase in β-NADH-dependent ROS signalling (Kumasaka et al. 1999). The resulting hypoxia-induced Ca2+ release from the SR is then thought to trigger capacitative calcium entry and/or voltage-dependent calcium entry, thus increasing [Ca2+]i and therefore amplifying tension generation (Robertson et al. 2000; Sweeney & Yuan, 2000; Snetkov et al. 2003; Wang et al. 2004). Alternatively, hydrogen peroxide has been shown to activate phospholipase C (PLC) (Gonzalez-Pacheco et al. 2002). Phospholipase C generates diacylglycerol (DAG) and inositol trisphosphate (IP3) from phosphatidylinositol bisphosphate (PIP2). Recently, hypoxia-induced DAG has been shown to activate membrane-bound transient receptor potential channel 6 (TRPC6) channels, resulting in Na+ influx, membrane depolarization and activation of L-type, voltage-gated calcium channels (Weissmann et al. 2006).
Unfortunately, the technical limitations of the tools used to assess oxidant stress have fuelled the discrepancies regarding ROS signalling during hypoxia. Fluorescent probes such as DCFH and dihydroethidium lack specificity (Thannickal & Fanburg, 2000) and can accumulate within organelles. Autoxidation and limited intracellular access interfere with the ability of lucigenin or luminol to detect intracellular oxidants (Spasojevic et al. 2000). None of these probes exhibits ratiometric fluorescence, so that a change in intracellular dye concentration or fluorescence path length caused by a change in cell volume alters fluorescence intensity unrelated to changes in ROS. Therefore, to address these problems, ratiometric, redox-sensitive probes were recently developed to provide assessment of ROS signalling during hypoxia. One such probe uses fluorescence resonance energy transfer (FRET) and consists of enhanced cyan and yellow fluorescent protein motifs (CFP and YFP, respecitively) linked by the redox-dependent regulatory domain from the bacterial heat shock protein HSP-33 (HSP-FRET; Janda et al. 2004). The HSP-33 domain contains four highly conserved cysteine residues co-ordinating a zinc-binding domain. Oxidation of the thiols leads to release of zinc and the formation of two disulphides (Barbirz et al. 2000), resulting in a structural change in the optical coupling of CFP and YFP. When expressed in cells, this HSP-FRET provides a sensitive, real-time assessment of changes in redox conditions in the cytosol in response to hypoxia (Fig. 1; Waypa et al. 2006). Furthermore, this response was attenuated by the overexpression of either of the antioxidants catalase or glutathione peroxidase (Waypa et al. 2006).
Mitochondria increase ROS signalling during hypoxia
During respiration, reducing equivalents generated in glycolysis or the Krebs cycle are passed along the electron transport chain (ETC), concluding at complex IV (cytochrome oxidase), where molecular O2 is reduced to H2O. However, superoxide can be generated at sites upstream from complex IV when single electrons escape from the various transport proteins (Chance & Williams, 1955). A predominant site of superoxide generation involves the Qo site, near the outer surface of the inner mitochondrial membrane. Ubiquinol, carrying two electrons obtained from complex I or II, binds to complex III at the Qo site. After transferring one of its electrons to the Rieske iron–sulphur protein (RISP), ubisemiquinone is formed (Fig. 2; Iwata et al. 1998; Chen et al. 2003; Moghaddas et al. 2003; Sun & Trumpower, 2003). Ubisemiquinone normally transfers its remaining electron to the b cytochromes in complex III. However, this free radical can alternatively transfer an electron to O2, yielding superoxide. How this mechanism of electron transfer to molecular O2 could paradoxically increase during hypoxia was first predicted by Misra and Fridovich, who postulated that an increase in the reduction state of the mitochondrial ETC during hypoxia would promote ROS generation despite the decrease in O2 substrate (Misra & Fridovich, 1972).
Though the mechanism by which hypoxia augments ROS signalling from the mitochondrial ETC under conditions of hypoxia remains unresolved, three potential mechanisms have been proposed (Schumacker, 2005). The Vectoral Transport hypothesis suggests that hypoxia may increase the relative release of ROS from complex III towards the intermembrane space, while decreasing the relative release towards the matrix. The Semiquinone Lifetime hypothesis suggests that a decrease in O2 interaction with protein or lipids at complex III could prolong the lifetime of ubisemiquinone at complex III. Finally, the Oxygen Access hypothesis suggests that hypoxia might increase the access of O2 to the semiquinone radical moiety at complex III. In each of these mechanisms, membrane O2 levels would affect lipid–protein structure so as to increase electron transfer from ubisemiquinone to O2, yielding an increase in superoxide release to the cytosol despite a decrease in the availability of oxygen.
The theory that HPV requires electron transport in the proximal but not in the distal region of the ETC was first suggested by Acher and co-workers based on results suggesting that HPV was due to a decrease in ROS signalling (Archer et al. 1993). More recent studies have also suggested the involvement of the proximal region of the ETC; however, results from these studies point to an increase in ROS signalling during HPV (Leach et al. 2001; Waypa et al. 2001, 2002; Weissmann et al. 2003). Inhibition of complex I by rotenone or diphenylene iodonium or of complex III by myxothiazol abrogates HPV (Waypa et al. 2001, 2002; Weissmann et al. 2003; Wang et al. 2007), while inhibitors acting at more distal sites in the ETC, such as cyanide or antimycin A, fail to inhibit the response (Fig. 2). Furthermore, genetic deletion of key units of the mitochondrial ETC in different cell types by our laboratory and others provides substantiating evidence that the ETC plays a physiologically conserved role in hypoxia-induced ROS signalling and hypoxic responses such as the stabilization of hypoxia-inducible factors (Guzy et al. 2005; Mansfield et al. 2005). Recently, the relationship between hypoxia-induced mitochondrial ROS signalling and the increase in [Ca2+]i was explored using the ratiometric, redox-sensitive HSP-FRET sensor and YC2.3, a FRET-based ratiometric Ca2+ sensor, respectively (Waypa et al. 2006). Once again, inhibition of complex III with myxothiazol attenuated the hypoxia-induced increases in ROS signalling and [Ca2+]i, whereas the complex IV inhibitor cyanide had no effect. Furthermore, attenuation of the hypoxia-induced ROS signal through the overexpression of either of the antioxidants catalase or glutathione peroxidase also prevented the increase in [Ca2+]i. Finally, these studies were the first to demonstrate a hypoxia-induced increase in ROS signalling, as measured by the HSP-FRET sensor, along with a corresponding increase in [Ca2+]i, as measured by fura-2 AM in the same PASMC (Waypa et al. 2006). Collectively, these findings are consistent with a role for increased mitochondrial ROS production in HPV.
Concluding remarks
Achieving a concensus concerning whether hypoxic pulmonary vasoconstriction is triggered by a decrease or an increase in mitochondria-dependent ROS signalling has been difficult because of the limitations of the early tools used to assess this mechansim. However, recent investigations using the ratiometric, redox-sensitive HPS-FRET probe, as well as unpublished results from others, provide increasing evidence that a paradoxical increase in mitochondria-dependent ROS signalling is involved in HPV, which initiates a chain of events resulting in the pulmonary arterial vasoconstriction response. Furthermore, with the continued development of targeted ratiomentric, redox-sensitive probes, able to assess changes in hypoxia-induced ROS signalling in subcellular compartments, we may one day be able to integrate the past discrepancies of measured hypoxia-induced ROS signalling into a complete story. Finally, the availability of genetic tools to modulate ROS production and ROS scavenging should bring to an end our previous reliance on pharmacological agents and their dose-dependant effects which for years have resulted in different laboratories reaching conflicting conclusions based on their use. Therefore, the book on the subject of HPV is far from closed; however, we are moving closer towards achieving definitive results and thus reaching an overall consensus on this important mechanism.
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