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(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

Sébastien Bonnet, PhD; Evangelos D. Michelakis, MD; Christopher J. Porter, BSc; Miguel A. Andrade-Navarro, BA, PhD; Bernard Thébaud, MD, PhD; Sandra Bonnet, MS; Alois Haromy, BSc; Gwyneth Harry, BSc; Rohit Moudgil, MS; M. Sean McMurtry, MD; E. Kenneth Weir, MD; Stephen L. Archer, MD

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.

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