Published online before print May 30, 2006, doi: 10.1161/CIRCULATIONAHA.105.609008
(Circulation. 2006;113:2630-2641.)
© 2006 American Heart Association, Inc.
Vascular Medicine |
An Abnormal Mitochondrial–Hypoxia Inducible Factor-1
–Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats
Similarities to Human Pulmonary Arterial Hypertension
From the Vascular Biology Group, Division of Cardiology (S.B., E.D.M., B.T., S.B., A.H., G.H., R.M., M.S.M., S.L.A.), Physiology Department (S.L.A.), and Department of Pediatrics (B.T.), University of Alberta, Edmonton, Canada; Department of Medicine (Cardiology) (E.K.W.), Minneapolis Veterans Affairs Medical Center, Minneapolis, Minn; and Ontario Genomics Innovation Centre (C.J.P., M.A.A.-N.), Ottawa Health Research Institute, Ottawa, Ontario.
Correspondence to Stephen L. Archer, MD, FRCP, FAHA, University of Alberta, WMC 2C2.36, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7. E-mail sarcher{at}cha.ab.ca
Received December 19, 2005; revision received March 31, 2006; accepted April 3, 2006.
Background— The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain.
Methods and Results— Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by &60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1
), which then inhibited expression of oxygen-sensitive, voltage-gated K+ channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H2O2) or blocking HIF-1 activation (dominant-negative HIF-1) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3 (an HIF-1 repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1 activation; and reduced expression/activity of HIF-3, cytochrome c oxidase, and superoxide dismutase-2.
Conclusions— FHRs have a chromosome 1 abnormality that disrupts a mitochondria-ROS-HIF-Kv pathway, leading to PAH. Similar abnormalities occur in idiopathic human PAH. This study reveals an intersection between oxygen-sensing mechanisms and PAH. The mitochondria-ROS-HIF-Kv pathway offers new targets for PAH therapy.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  T. van Haaften, R. Byrne, S. Bonnet, G. Y. Rochefort, J. Akabutu, M. Bouchentouf, G. J. Rey-Parra, J. Galipeau, A. Haromy, F. Eaton, et al. Airway Delivery of Mesenchymal Stem Cells Prevents Arrested Alveolar Growth in Neonatal Lung Injury in Rats Am. J. Respir. Crit. Care Med., December 1, 2009; 180(11): 1131 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Stenmark, B. Meyrick, N. Galie, W. J. Mooi, and I. F. McMurtry Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1013 - L1032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Roth, M. Rupp, S. Hofmann, M. Mittal, B. Fuchs, N. Sommer, N. Parajuli, K. Quanz, D. Schubert, E. Dony, et al. Heme Oxygenase-2 and Large-Conductance Ca2+-activated K+ Channels: Lung Vascular Effects of Hypoxia Am. J. Respir. Crit. Care Med., August 15, 2009; 180(4): 353 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dromparis and E. D. Michelakis A redox-metabolic-electrical remodeling in the diseased left and right ventricle: direct clinical implications in heart disease and beyond. Focus on "Role of {gamma}-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts" Am J Physiol Cell Physiol, August 1, 2009; 297(2): C231 - C234. [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Prows, A. V. Winterberg, W. J. Gibbons Jr., B. B. Burzynski, C. Liu, and T. G. Nick Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time Physiol Genomics, July 9, 2009; 38(2): 158 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. W. Morrell, S. Adnot, S. L. Archer, J. Dupuis, P. Lloyd Jones, M. R. MacLean, I. F. McMurtry, K. R. Stenmark, P. A. Thistlethwaite, N. Weissmann, et al. Cellular and molecular basis of pulmonary arterial hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S20 - S31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. V. McLaughlin, S. L. Archer, D. B. Badesch, R. J. Barst, H. W. Farber, J. R. Lindner, M. A. Mathier, M. D. McGoon, M. H. Park, R. S. Rosenson, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1573 - 1619. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, V. V. McLaughlin, S. L. Archer, D. B. Badesch, R. J. Barst, H. W. Farber, J. R. Lindner, M. A. Mathier, M. D. McGoon, M. H. Park, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in Collaboration With the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association Circulation, April 28, 2009; 119(16): 2250 - 2294. [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Michelakis Soluble guanylate cyclase stimulators as a potential therapy for PAH: enthusiasm, pragmatism and concern Eur. Respir. J., April 1, 2009; 33(4): 717 - 721. [Full Text] [PDF]
|
|
|
|
 |
|
 S. H.H. Chan, K. L.H. Wu, A. Y.W. Chang, M.-H. Tai, and J. Y.H. Chan Oxidative Impairment of Mitochondrial Electron Transport Chain Complexes in Rostral Ventrolateral Medulla Contributes to Neurogenic Hypertension Hypertension, February 1, 2009; 53(2): 217 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Poburko, C.-H. Liao, C. van Breemen, and N. Demaurex Mitochondrial Regulation of Sarcoplasmic Reticulum Ca2+ Content in Vascular Smooth Muscle Cells Circ. Res., January 2, 2009; 104(1): 104 - 112. [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]
|
|
|
|
 |
|
 Y.-B. Shui, J. M. Arbeit, R. S. Johnson, and D. C. Beebe HIF-1: An Age-Dependent Regulator of Lens Cell Proliferation Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 4961 - 4970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J Zhang, P. T Toth, D. Urboniene, and S. L Archer Abstract 2625: The Demethylating Agent 5-aza-2'deoxycytidine (Decitabine) Restores Superoxide Dismutase 2 (SOD2) Expression and Reactive Oxygen Species Production in the Pulmonary Arteries of Fawn-hooded Rats with Pulmonary Hypertension Circulation, October 28, 2008; 118(18_MeetingAbstracts): S_755 - S_756.
|
|
|
|
|
|
E. D. Michelakis, M. R. Wilkins, and M. Rabinovitch Emerging Concepts and Translational Priorities in Pulmonary Arterial Hypertension Circulation, September 30, 2008; 118(14): 1486 - 1495. [Full Text] [PDF]
|
|
|
|
|
|
G. Kwapiszewska, M. Wygrecka, L. M. Marsh, S. Schmitt, R. Trosser, J. Wilhelm, K. Helmus, B. Eul, A. Zakrzewicz, H. A. Ghofrani, et al. Fhl-1, a New Key Protein in Pulmonary Hypertension Circulation, September 9, 2008; 118(11): 1183 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Rey-Parra, S. L. Archer, R. D. Bland, K. H. Albertine, D. P. Carlton, S.-C. Cho, B. Kirby, A. Haromy, F. Eaton, X. Wu, et al. Blunted Hypoxic Pulmonary Vasoconstriction in Experimental Neonatal Chronic Lung Disease Am. J. Respir. Crit. Care Med., August 15, 2008; 178(4): 399 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nagendran, V. Gurtu, D. Z. Fu, J. R.B. Dyck, A. Haromy, D. B. Ross, I. M. Rebeyka, and E. D. Michelakis A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted J. Thorac. Cardiovasc. Surg., July 1, 2008; 136(1): 168 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Mehta, J. L. Campian, J. Guardiola, J. A. Cabrera, E. K. Weir, and J. W. Eaton Generation of Oxidants by Hypoxic Human Pulmonary and Coronary Smooth-Muscle Cells Chest, June 1, 2008; 133(6): 1410 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Mingone, M. Ahmad, S. A. Gupte, J. L. Chow, and M. S. Wolin Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1244 - H1250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Weir, M. Obreztchikova, and Z. Hong Fenfluramine: riddle or Rosetta stone? Eur. Respir. J., February 1, 2008; 31(2): 232 - 235. [Full Text] [PDF]
|
|
|
|
|
|
E. M. Whitman, S. Pisarcik, T. Luke, M. Fallon, J. Wang, J. T. Sylvester, G. L. Semenza, and L. A. Shimoda Endothelin-1 mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytes Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L309 - L318. [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]
|
|
|
|
|
|
M. S. McMurtry, S. Bonnet, E. D. Michelakis, S. Bonnet, A. Haromy, and S. L. Archer Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L933 - L940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bonnet, G. Rochefort, G. Sutendra, S. L. Archer, A. Haromy, L. Webster, K. Hashimoto, S. N. Bonnet, and E. D. Michelakis The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted PNAS, July 3, 2007; 104(27): 11418 - 11423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Sehgal and S. Mukhopadhyay Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs? Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H77 - H85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Y. Rochefort and E. D. Michelakis COUNTERPOINT: RELEASE OF AN ENDOTHELIUM-DERIVED VASOCONSTRICTOR AND RHOA/RHO KINASE-MEDIATED CALCIUM SENSITIZATION OF SMOOTH MUSCLE CELL CONTRACTION ARE NOT THE MAIN EFFECTORS FOR FULL AND SUSTAINED HPV J Appl Physiol, May 1, 2007; 102(5): 2072 - 2075. [Full Text] [PDF]
|
|
|
|
|
|
H. Kajimoto, K. Hashimoto, S. N. Bonnet, A. Haromy, G. Harry, R. Moudgil, T. Nakanishi, I. Rebeyka, B. Thebaud, E. D. Michelakis, et al. Oxygen Activates the Rho/Rho-Kinase Pathway and Induces RhoB and ROCK-1 Expression in Human and Rabbit Ductus Arteriosus by Increasing Mitochondria-Derived Reactive Oxygen Species: A Newly Recognized Mechanism for Sustaining Ductal Constriction Circulation, April 3, 2007; 115(13): 1777 - 1788. [Abstract] [Full Text] [PDF]
|
|