An Abnormal Mitochondrial–Hypoxia Inducible Factor-1α–Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats

Abstract

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 Ϸ60 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 ϩ 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 H 2 O 2 ) 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

Hypoxia and chronic lung disease

“…An extension of this paradigm is the evidence that the pulmonary vascular remodeling in severe PH involves elements of abnormal angiogenesis [40], and it resembles that seen in neoplastic cells [41]. HIF-1α controls several features involved in angiogenesis and cancer cell growth, including mitochondria function, which have been validated recently in studies of experimental PH [42]. Mitochondria of PASMCs are different from their systemic counterpart, as they have lower respiratory rates, are more depolarized, have more manganese superoxide dismutase (MnSOD), and produce more hydrogen peroxide [43].…”

Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

“…While oxidative stress could contribute to depleting sGC heme, it is not currently known if heme levels in smooth muscle also decrease as a result of increased HO-1 activity and/or a reduced level of heme biosynthesis. Mitochondrial dysfunction is seen in many vascular diseases, including pulmonary hypertension (5), and this could be hypothesized to be a factor in impairing the biosynthesis of heme by this organelle. While it has been observed that a key beneficial effects of HO-1 induction on reversing vascular dysfunction in vivo can originate from its lowering of superoxide levels (34), sGC heme depletion by HO-1 could a factor where vascular disease processes have elevated HO-1 levels and impaired vascular regulation by the NO-sGC system is observed.…”

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…Impaired glucose metabolism has been described in SMCs and ECs in both humans and rodent models of PAH (Bonnet et al, 2006;Fijalkowska et al, 2010;Xu et al, 2007). There are many pathological implications of this phenotype; 1) suppressed apoptosis, 2) impaired signaling of pro-proliferative downstream targets (ie.…”

“…The use of metabolic modulator, DCA, for treatment of PAH has shown promising results in animal models (McMurtry et al, 2004;Bonnet et al, 2006). Additionally, DCA has been used as a therapy for metabolic disease and lactic acidosis, which lowers the barrier for clinical trials and translation into PAH patients Michelakis et al, 2013).…”