REBUTTAL FROM DR. WARD

Abstract

POINT-COUNTERPOINTREBUTTAL FROM DR. WARDPublished Online:01 Sep 2006https://doi.org/10.1152/japplphysiol.00480b.2006MoreSectionsPDF (38 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Our adversaries claim they only have to show that the balance of evidence favors the aggregate of all other hypotheses to win the debate. Apart from the difficulty of “aggregating” such disparate hypotheses, this implies that all definitively exclude an increase in ROS. Not necessarily true; for example, a recent report that hypoxia activates AMP kinase via increased ROS, independent of changes in nucleotides (5).Understandably, the thrust of their article concerns the case for the Redox hypothesis, the central tenet of which is that the primary response to hypoxia is a fall in ROS and subsequent reduction and inhibition of KV channels. However, it has been suggested that the depolarization associated with HPV may actually be secondary to activation of non-selective cation channels (NSCC) by, for example, store release, as NSCC blockers and ryanodine essentially abolish HPV, whereas L-type blockers are generally less effective (1, 9). Apart from K+ channels, all other components of the “executive” of HPV are known to be activated by increased ROS, e.g., ryanodine channels, NSCCs, and upstream activators of SOC, ROC, and Rho kinase such as Src (e.g., Refs. 6–8).The lack of vasoconstriction during hyperoxia is not absolutely surprising, as hyperoxia may preferentially promote NAD(P)H oxidase ROS production (4), primarily extracellular and possibly prorelaxant, and other O2-dependent mechanisms such as NO synthase. The real estate cry of “location, location!” is of pre-eminent importance; certainly the close approximation of peripheral mitochondria with SR and sarcolemma is optimal for intracellular hypoxic/ROS/Ca2+ signaling (7). Use of novel, organelle-targeted ROS probes may well elucidate these aspects. Similar reservations can be applied to the use of powerful and promiscuous oxidizing and reducing agents such as DTNB and dithiotheitol—these may well affect K+ channels, but do they mimic physiology or industry?The very recent study concerning mitochondrial defects in Fawn-Hooded rats (2) is intriguing, but could possibly be interpreted otherwise; such mitochondrial damage is reminiscent of Ca2+ overload, which can actually increase mitochondrial ROS production. Indeed, notwithstanding the reported measurements of ROS, and directly contradicting this paper, numerous reports have shown that HIF is activated by increased ROS (e.g., Refs. 3, 6).Finally, our chums try to hoist us with our own petard with a quote from the introduction to our recent review. Tut tut. The quote is truncated, since it is followed by the all important word “However …”, which leads to the meat of the review (1).REFERENCES1 Aaronson PI, Robertson TP, Knock GA, Becker S, Lewis TH, Snetkov V, and Ward JP. Hypoxic pulmonary vasoconstriction: mechanisms and controversies. J Physiol 570: 53–58, 2006.Crossref | PubMed | ISI | Google Scholar2 Bonnet S, Michelakis E, Porter C, and et al. An abnormal mitochondrial-HIF1α-Kv channel pathway disrupts oxygen-sensing and triggers pulmonary arterial hypertension (PAH) in fawn-hooded rats: similarities to human PAH. Circulation. In press.Google Scholar3 Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, and Simon MC. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1: 393–399, 2005.Crossref | PubMed | ISI | Google Scholar4 Parinandi NL, Kleinberg MA, Usatyuk PV, Cummings RJ, Pennathur A, Cardounel AJ, Zweier JL, Garcia JG, and Natarajan V. Hyperoxia-induced NAD(P)H oxidase activation and regulation by MAP kinases in human lung endothelial cells. Am J Physiol Lung Cell Mol Physiol 284: L26–L38, 2003.Link | ISI | Google Scholar5 Quintero M, Colombo SL, Godfrey A, and Moncada S. Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA 103: 5379–5384, 2006.Crossref | PubMed | ISI | Google Scholar6 Sato H, Sato M, Kanai H, Uchiyama T, Iso T, Ohyama Y, Sakamoto H, Tamura J, Nagai R, and Kurabayashi M. Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells. Cardiovasc Res 67: 714–722, 2005.Crossref | PubMed | ISI | Google Scholar7 Ward JP, Snetkov VA, and Aaronson PI. Calcium, mitochondria and oxygen sensing in the pulmonary circulation. Cell Calcium 36: 209–220, 2004.Crossref | PubMed | ISI | Google Scholar8 Waring P. Redox active calcium ion channels and cell death. Arch Biochem Biophys 434: 33–42, 2005.Crossref | PubMed | ISI | Google Scholar9 Weigand LA, Foxson J, Wang J, Shimoda LA, and Sylvester JT. Inhibition of hypoxic pulmonary vasoconstriction by store-operated Ca2+ and nonselective cation channel antagonists. Am J Physiol Lung Cell Mol Physiol [doi:10.1152/ajplung.00044.2005]Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 101Issue 3September 2006Pages 998-998 Copyright & PermissionsCopyright © 2006 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00480b.2006History Published online 1 September 2006 Published in print 1 September 2006 Metrics