Circulation Research. 2002;91:719-726
Published online before print September 12, 2002, doi: 10.1161/01.RES.0000036751.04896.F1
Published online before print September 12, 2002, doi: 10.1161/01.RES.0000036751.04896.F1
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2002 American Heart Association, Inc.
Cellular Biology |
Mitochondrial Reactive Oxygen Species Trigger Calcium Increases During Hypoxia in Pulmonary Arterial Myocytes
From Pulmonary and Critical Care Medicine (G.B.W., M.M.M., P.T.M., P.T.S.) and the Pediatrics Section of Neonatology (J.D.M., C.B.), The University of Chicago, Chicago, Ill.
Correspondence to Paul T. Schumacker, PhD, Department of Medicine, MC6026, The University of Chicago, 5841 South Maryland Ave, Chicago, IL 60637. E-mail pschumac{at}medicine.bsd.uchicago.edu
We hypothesized that mitochondria function as the O2 sensors underlying hypoxic pulmonary vasoconstriction by releasing reactive oxygen species (ROS) from complex III of the electron transport chain (ETC). We have previously found that antioxidants or inhibition of the proximal region of the ETC attenuates hypoxic pulmonary vasoconstriction in rat lungs and blocks hypoxia-induced contraction of isolated pulmonary arterial (PA) myocytes. To determine whether the hypoxia-induced increases in mitochondrial ROS act to trigger calcium increases, we measured changes in cytosolic calcium ([Ca2+]i) using fura 2-AM (fluorescence at 340/380 nm) during perfusion with hypoxic media (PO2 12 mm Hg). Hypoxia caused an increase in fura 2 fluorescence, indicating an increase in [Ca2+]i. In superfused PA myocytes, diphenyleneiodonium, rotenone, and myxothiazol, which inhibit the proximal region of the ETC, attenuated hypoxia-induced calcium increases. Antimycin A and cyanide, which inhibit the distal region of the ETC, failed to abolish hypoxia-induced [Ca2+]i increases. To test whether mitochondrial H2O2 is required to trigger [Ca2+]i increases, catalase was overexpressed in PA myocytes with the use of a recombinant adenovirus. Catalase overexpression attenuated hypoxia-induced increases in [Ca2+]i, suggesting that H2O2 acts upstream from calcium increases during hypoxia. These results support the conclusion that mitochondria function as O2 sensors during hypoxia and demonstrate that ROS generated in the proximal region of the ETC act as second messengers to trigger calcium increases in PA myocytes during acute hypoxia.
Key Words: reactive oxygen species • hypoxia • redox signaling • pulmonary circulation • oxidants
This article has been cited by other articles:
 |
|
 |
|
  N. Weissmann, S. Hackemack, B. K. Dahal, S. S. Pullamsetti, R. Savai, M. Mittal, B. Fuchs, T. Medebach, R. Dumitrascu, M. v. Eickels, et al. The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L658 - L665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ahmad, X. Zhao, M. R. Kelly, S. Kandhi, O. Perez, N. G. Abraham, and M. S. Wolin Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1453 - H1461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Firth, D. V. Gordienko, K. H. Yuill, and S. V. Smirnov Cellular localization of mitochondria contributes to Kv channel-mediated regulation of cellular excitability in pulmonary but not mesenteric circulation Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L347 - L360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hori and K. Nishida Oxidative stress and left ventricular remodelling after myocardial infarction Cardiovasc Res, February 15, 2009; 81(3): 457 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Sommer, A. Dietrich, R. T. Schermuly, H. A. Ghofrani, T. Gudermann, R. Schulz, W. Seeger, F. Grimminger, and N. Weissmann Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms Eur. Respir. J., December 1, 2008; 32(6): 1639 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Knock, V. A. Snetkov, Y. Shaifta, S. Drndarski, J. P.T. Ward, and P. I. Aaronson Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery Cardiovasc Res, December 1, 2008; 80(3): 453 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Hirenallur-S., S. T. Haworth, J. T. Leming, J. Chang, G. Hernandez, J. B. Gordon, and N. J. Rusch Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L915 - L924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Archer, M. Gomberg-Maitland, M. L. Maitland, S. Rich, J. G. N. Garcia, and E. K. Weir Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H570 - H578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. B. Waypa and P. T. Schumacker Oxygen sensing in hypoxic pulmonary vasoconstriction: using new tools to answer an age-old question Exp Physiol, January 1, 2008; 93(1): 133 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, L. Weigand, J. Foxson, L. A. Shimoda, and J. T. Sylvester Ca2+ signaling in hypoxic pulmonary vasoconstriction: effects of myosin light chain and Rho kinase antagonists Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L674 - L685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Platoshyn, Y. Yu, E. A Ko, C. V. Remillard, and J. X.-J. Yuan Heterogeneity of hypoxia-mediated decrease in IK(V) and increase in [Ca2+]cyt in pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L402 - L416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-J. Lin, X.-R. Yang, Y.-N. Cao, and J. S. K. Sham Hydrogen peroxide-induced Ca2+ mobilization in pulmonary arterial smooth muscle cells Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1598 - L1608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. X. Zhang and D. D. Gutterman Mitochondrial reactive oxygen species-mediated signaling in endothelial cells Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2023 - H2031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Weissmann, A. Dietrich, B. Fuchs, H. Kalwa, M. Ay, R. Dumitrascu, A. Olschewski, U. Storch, M. Mederos y Schnitzler, H. A. Ghofrani, et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange PNAS, December 12, 2006; 103(50): 19093 - 19098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Camello-Almaraz, P. J. Gomez-Pinilla, M. J. Pozo, and P. J. Camello Mitochondrial reactive oxygen species and Ca2+ signaling Am J Physiol Cell Physiol, November 1, 2006; 291(5): C1082 - C1088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. B. Waypa, R. Guzy, P. T. Mungai, M. M. Mack, J. D. Marks, M. W. Roe, and P. T. Schumacker Increases in Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Induced Calcium Responses in Pulmonary Artery Smooth Muscle Cells Circ. Res., October 27, 2006; 99(9): 970 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. T. Ward Point:Counterpoint: Hypoxic pulmonary vasoconstriction is/is not mediated by increased production of reactive oxygen species J Appl Physiol, September 1, 2006; 101(3): 993 - 995. [Full Text] [PDF]
|
|
|
|
|
|
R. D. Guzy and P. T. Schumacker Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia Exp Physiol, September 1, 2006; 91(5): 807 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Weissmann, N. Sommer, R. T. Schermuly, H. A. Ghofrani, W. Seeger, and F. Grimminger Oxygen sensors in hypoxic pulmonary vasoconstriction Cardiovasc Res, September 1, 2006; 71(4): 620 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Rhoads, A. L. Umbach, C. C. Subbaiah, and J. N. Siedow Mitochondrial Reactive Oxygen Species. Contribution to Oxidative Stress and Interorganellar Signaling Plant Physiology, June 1, 2006; 141(2): 357 - 366. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Brueckl, S. Kaestle, A. Kerem, H. Habazettl, F. Krombach, H. Kuppe, and W. M. Kuebler Hyperoxia-Induced Reactive Oxygen Species Formation in Pulmonary Capillary Endothelial Cells In Situ Am. J. Respir. Cell Mol. Biol., April 1, 2006; 34(4): 453 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Weissmann, S. Zeller, R. U. Schafer, C. Turowski, M. Ay, K. Quanz, H. A. Ghofrani, R. T. Schermuly, L. Fink, W. Seeger, et al. Impact of Mitochondria and NADPH Oxidases on Acute and Sustained Hypoxic Pulmonary Vasoconstriction Am. J. Respir. Cell Mol. Biol., April 1, 2006; 34(4): 505 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Platoshyn, E. E. Brevnova, E. D. Burg, Y. Yu, C. V. Remillard, and J. X.-J. Yuan Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells Am J Physiol Cell Physiol, March 1, 2006; 290(3): C907 - C916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Du, M. Frazier, T. J. McMahon, and J. P. Eu Redox Activation of Intracellular Calcium Release Channels (Ryanodine Receptors) in the Sustained Phase of Hypoxia-Induced Pulmonary Vasoconstriction Chest, December 1, 2005; 128(6_suppl): 556S - 558S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. BAILEY-SERRES and R. CHANG Sensing and Signalling in Response to Oxygen Deprivation in Plants and Other Organisms Ann. Bot., September 1, 2005; 96(4): 507 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Gutterman Mitochondria and Reactive Oxygen Species: An Evolution in Function Circ. Res., August 19, 2005; 97(4): 302 - 304. [Full Text] [PDF]
|
|
|
|
|
|
M. S. Wolin, M. Ahmad, and S. A. Gupte Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L159 - L173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Sun, N.-P. Wang, F. Kerendi, M. Halkos, H. Kin, R. A. Guyton, J. Vinten-Johansen, and Z.-Q. Zhao Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+ overload Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1900 - H1908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kimura, G.-X. Zhang, A. Nishiyama, T. Shokoji, L. Yao, Y.-Y. Fan, M. Rahman, and Y. Abe Mitochondria-Derived Reactive Oxygen Species and Vascular MAP Kinases: Comparison of Angiotensin II and Diazoxide Hypertension, March 1, 2005; 45(3): 438 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Dong, Q. Li, S.-c. Lyu, A. M. Krensky, and C. Clayberger A novel apoptosis pathway activated by the carboxyl terminus of p21 Blood, February 1, 2005; 105(3): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Moudgil, E. D. Michelakis, and S. L. Archer Hypoxic pulmonary vasoconstriction J Appl Physiol, January 1, 2005; 98(1): 390 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. B. Waypa and P. T. Schumacker Hypoxic pulmonary vasoconstriction: redox events in oxygen sensing J Appl Physiol, January 1, 2005; 98(1): 404 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. H. Mauban, C. V. Remillard, and J. X.-J. Yuan Hypoxic pulmonary vasoconstriction: role of ion channels J Appl Physiol, January 1, 2005; 98(1): 415 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Mansfield, M. C. Simon, and B. Keith Hypoxic reduction in cellular glutathione levels requires mitochondrial reactive oxygen species J Appl Physiol, October 1, 2004; 97(4): 1358 - 1366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Kerbaul, P. Van der Linden, S. Pierre, B. Rondelet, C. Melot, S. Brimioulle, and R. Naeije Prevention of Hemodilution-Induced Inhibition of Hypoxic Pulmonary Vasoconstriction by N-Acetylcysteine in Dogs Anesth. Analg., August 1, 2004; 99(2): 547 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. DOUGHERTY, L. A. KUBASIAK, D. P. FRAZIER, H. LI, W.-CHENG. XIONG, N. H. BISHOPRIC, and K. A. WEBSTER Mitochondrial signals initiate the activation of c-Jun N-terminal kinase (JNK) by hypoxia-reoxygenation FASEB J, July 1, 2004; 18(10): 1060 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Matsui, T. Shimosawa, K. Itakura, X. Guanqun, K. Ando, and T. Fujita Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia Circulation, May 11, 2004; 109(18): 2246 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Cheranov and J. H. Jaggar Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries J. Physiol., May 1, 2004; 556(3): 755 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hagen, C. T. Taylor, F. Lam, and S. Moncada Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1{alpha} Science, December 12, 2003; 302(5652): 1975 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Weissmann, N. Ebert, M. Ahrens, H. A. Ghofrani, R. T. Schermuly, J. Hanze, L. Fink, F. Rose, J. Conzen, W. Seeger, et al. Effects of Mitochondrial Inhibitors and Uncouplers on Hypoxic Vasoconstriction in Rabbit Lungs Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 721 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Cowan, M. Jones, L. M. Garcia, S. Noria, P. J. del Nido, and F. X. McGowan Jr Hypoxia and Stretch Regulate Intercellular Communication in Vascular Smooth Muscle Cells Through Reactive Oxygen Species Formation Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1754 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-P. Tzeng, R.-S. Yang, T.-H. Ueng, S.-Y. Lin-Shiau, and S.-H. Liu Motorcycle Exhaust Particulates Enhance Vasoconstriction in Organ Culture of Rat Aortas and Involve Reactive Oxygen Species Toxicol. Sci., September 1, 2003; 75(1): 66 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Teshima, M. Akao, S. P. Jones, and E. Marban Uncoupling Protein-2 Overexpression Inhibits Mitochondrial Death Pathway in Cardiomyocytes Circ. Res., August 8, 2003; 93(3): 192 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Resta Hypoxic regulation of nitric oxide signaling in vascular smooth muscle Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L293 - L295. [Full Text] [PDF]
|
|
|
|
|
|
J. Q. Liu, J. S. K. Sham, L. A. Shimoda, P. Kuppusamy, and J. T. Sylvester Hypoxic constriction and reactive oxygen species in porcine distal pulmonary arteries Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L322 - L333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S.K. Sham Hypoxic Pulmonary Vasoconstriction: Ups and Downs of Reactive Oxygen Species Circ. Res., October 18, 2002; 91(8): 649 - 651. [Full Text] [PDF]
|
|