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Am J Physiol Heart Circ Physiol 294: H570-H578, 2008. First published December 14, 2007; doi:10.1152/ajpheart.01324.2007
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INVITED REVIEW

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

Stephen L. Archer,2 Mardi Gomberg-Maitland,2 Michael L. Maitland,3 Stuart Rich,2 Joe G. N. Garcia,1 and E. Kenneth Weir4

1Department of Medicine, Sections of 2Cardiology and 3Hematology/Oncology, University of Chicago, Chicago, Illinois; and 4Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota


   ABSTRACT
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Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities occur, including endothelial injury/dysfunction, bone morphogenetic protein receptor-2 gene mutations, decreased expression of the O2-sensitive K+ channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) and nuclear factor-activating T cells], de novo expression of survivin, and increased expression/activity of both serotonin transporters and platelet-derived growth factor receptors. Together, these abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary artery smooth muscle cells (PASMCs). A possible unifying mechanism for PAH comes from studies of fawn-hooded rats, which manifest spontaneous PAH and impaired O2 sensing. PASMC mitochondria normally produce reactive O2 species (ROS) in proportion to PO2. Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H2O2, which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O2 sensing is mediated by this mitochondria-ROS-HIF-1{alpha}-Kv1.5 pathway. In PAH and cancer, mitochondrial metabolism and redox signaling are reversibly disordered, creating a pseudohypoxic redox state characterized by normoxic decreases in ROS, a shift from oxidative to glycolytic metabolism and HIF-1{alpha} activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1{alpha}-Kv1.5 pathway: 1) mitochondrial pyruvate dehydrogenase kinase activation, 2) SOD2 deficiency, and 3) fragmentation and/or hyperpolarization of the mitochondrial reticulum. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, corrects the mitochondrial abnormalities in experimental models of PAH and human cancer, causing a regression of both diseases. Mitochondrial abnormalities that disturb the ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.

hypoxia-inducible factor-1{alpha}; nuclear factor-activating T cells; voltage-gated potassium channels; fawn-hooded rats; mitochondrial fusion; pyruvate dehydrogenase kinase; lung cancer; reactive oxygen species; mitochondrial electron transport chain

PULMONARY ARTERIAL HYPERTENSION is a disease of the pulmonary vasculature, which occurs in a rare idiopathic form (sporadic-90%, familial-10%) and, more commonly, as a syndrome associated with connective tissue disease, congenital heart disease, anorexigen use (dexfenfluramine), portopulmonary disease, and human immunodeficiency virus (1). Predominantly affecting young women (female/male, 3/1), PAH has a 15% 1-yr mortality despite current therapy (91). The reported prevalence of idiopathic PAH (1/1,000,000) is likely an underestimation, due to lack of data on PAH syndromes in Africa and Asia, related to sickle cell disease and schistosomiasis, and to insensitivity of the history and physical examination, as suggested by the high prevalence of moderate pulmonary hypertension in active surveillance studies of high-risk cohorts with connective tissue diseases (71, 102).

Pathogenesis of PAH

PAH is a panvasculopathy. Abnormalities in each layer of the blood vessel contribute to this syndrome of obstructed, constricted small pulmonary arteries, right ventricular hypertrophy, and right ventricular failure. In the blood there is elevated plasma serotonin (40). In the endothelium there is a decreased ratio of vasodilators to constrictors (29, 88, 89). It is hypothesized that widespread endothelial apoptosis, early in PAH, culminates in the selection of apoptosis-resistant endothelial precursor cells that proliferate and ultimately form plexiform lesions later in the disease (80). In the media, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced, whereas apoptosis is depressed (54, 55, 57, 60). Many factors drive PASMC proliferation, including bone morphogenetic protein receptor-2 (BMPR-2) mutations (63) de novo expression of the anti-apoptotic protein survivin (54, 55), increased expression/activity of the serotonin transporter (SERT) (51), and increased expression/activity of platelet-derived growth factor receptor. Decreased expression of the voltage-gated channels Kv1.5 occurs in all forms of PAH and results in membrane depolarization and elevations of cytosolic K+ and Ca2+ (75, 106). Although the Kv channel link to the voltage-gated Ca2+ channel is very important, over time the expression/function of L-type Ca2+ channels is downregulated in experimental PAH (unpublished observation). The persistent elevation of cytosolic Ca2+ in PAH may also reflect upregulation of Trp6 channels (105). Interestingly, early in the evolution of PAH in BMPR-2 dominant-negative mice, before vascular remodeling occurs (104), an elevation of cytosolic Ca2+ is driven by activation of voltage-gated L-type Ca2+ channels (in response to loss of Kv1.5). We speculate that the Kv-membrane potential L-type Ca2+ channel pathway is downregulated later in the disease due to reduced protein expression of both channel types. This may explain why only 10% of PAH patients have a long-term response to Ca2+ channel blocker therapy (1).

PAH is also characterized by inappropriate transcription factor activation, notably normoxic activation of hypoxia-inducible factor (HIF-1{alpha}) (20) and Ca2+-calcineurin-dependent activation of nuclear factor-activating T cells (NFAT) (21). In the adventitia metalloprotease activation (31) causes architectural disruption, permitting cell migration and generating mitogenic peptides (tenascin) (31). Finally, infiltration of the lung with inflammatory cells (14, 22), endothelial-precursor cells (24), mesenchymal stem cells (35), and bone marrow-derived stem cells (74, 79, 108) occurs in PAH.

With the discovery of BMPR mutations in familial PAH, the cause of PAH appeared to be elucidated (33, 45). These mutations, which likely result in loss of function, favor PASMC proliferation (107). Consistent with this, a transgenic mouse with SMC-specific overexpression of a human dominant-negative BMPR-2 transgene develops PAH (101). However, BMPR-2 mutations occur in only 10% of PAH patients (66), and even in familial PAH, penetrance is low. Whereas modifier genes, such as SERT, may explain variable penetrance, BMPR-2 mutations only partially explain the cause of PAH (67). Moreover, BMPR-2 haploinsufficiency causes minimal (16) or no (50) PAH, although it enhances serotonin-mediated vasoconstriction (50). Finally, whereas BMPR-2 levels decline with the development of experimental PAH, adenoviral BMPR-2 gene therapy does not reduce PAH in the monocrotaline rat model (56). Although clearly associated with PAH, aberrant BMPR-2 function does not appear to be necessary or sufficient to cause PAH, suggesting that there could be another unifying cause for PAH.

Similarities Between Cancer and PAH

Otto Warburg, recipient of the 1931 Nobel Prize for his work on cellular respiration, proposed that a shift in glucose metabolism from oxidative phosphorylation to glycolysis (despite adequate O2 supply) was central to the cause/maintenance of cancers (93). New data show that PAH and cancer share the Warburg phenotype (19–21), indicated by mitochondrial hyperpolarization (19, 20), depressed activity of pyruvate dehydrogenase complex and depressed H2O2 production (54). This supports the hypothesis of Voelkel et al. (92) that PAH is between inflammation and cancer (92). We propose that in PAH (20) and cancer (13, 19, 52), the rapid, reversible metabolic/redox shifts that initiate hypoxic pulmonary vasoconstriction (HPV) (i.e., decreased ROS generation, increased reduction of redox couples such as NADH and glutathione, and Kv1.5 inhibition) (10, 99) become entrenched and occur independent of PO2 due to mitochondrial abnormalities that create a pseudohypoxic environment with glycolytic predominance and normoxic HIF-1{alpha} activation. This metabolic shift suppresses Kv1.5 expression, leading to membrane depolarization and an elevation of cytosolic K+ and Ca2+. In both PAH PASMC and cancer cell lines, this creates a proliferative, apoptosis-resistant phenotype.

Hypothesis

The intersection of O2 sensing, PAH, and cancer suggest a unifying hypothesis, namely that PAH is a mitochondrial disorder resulting from reversible disruption of the mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway (Fig. 1). This mitochondrial hypothesis builds on several prior theories: the Redox Hypothesis for HPV (10, 99), the Mitochondrial Metabolic Hypothesis of PAH (39, 55, 60), and the Warburg Hypothesis of carcinogenesis (19, 93) (Fig. 2).


Figure 1
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  		Fig. 1. Disruption of a mitochondrial O2-sensing pathway in cancer and pulmonary arterial hypertension (PAH). Several mitochondrial disorders [pathological activation of pyruvate dehydrogenase kinase (PDK) reduced SOD2 activity/expression, impaired mitochondrial fusion] limit the production of H2O2 and activate a downstream pathway that promotes excess cell proliferation and impairs apoptosis. Key abnormalities include normoxic activation of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) and decreased expression of the O2-sensitive Kv channel, Kv1.5. These abnormalities are shared, at least in part, by cancer, and each is a potential therapeutic target. Note the similarities to the pathway for O2 sensing that initiates hypoxic pulmonary vasoconstriction. ETC, electron transport chain; ROS, reactive O2 species; PASMCs, pulmonary artery smooth muscle cells; NFAT, nuclear factor-activating T cells, PDH, pyruvate dehydrogenase.

 

Figure 2
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  		Fig. 2. Changes in mitochondrial function in cancer and PAH. Schematic showing ROS generation from mitochondrial ETC complexes I and III. The superoxide is converted to H2O2 by SOD2. Dichloroacetate (DCA) can restore ROS production and mitochondrial membrane potential ({Delta}{Psi}m) by inhibiting PDK and thereby activating PDH with an attendant increase in intramitochondrial acetyl-CoA. This drives Krebs' cycle and increases availability of electron donors (NADH and FADH) for complex I and III within the mitochondria. Dichloroacetate effectively regresses experimental PAH and human cancers by exploiting a shared abnormality (PDK activation). TCA, tricarboxylic acid cycle; F1Fo, ATP synthase; ANT = ADP/ATP antiporter.

 
Impaired Mitochondrial Fusion in PAH

The mitochondrial reticulum permeates the PASMC cytosol. With its close proximity to the plasma and nuclear membranes, it is well positioned to coordinate redox signaling. Mitochondria not only move within the cytosol (15, 17, 18, 34, 81) but also rapidly join and break apart (fusion and fission) processes that are regulated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-like proteins, including mitofusin-1 and -2 (17, 81). Fusion is an important mechanism for redistribution of mitochondrial proteins/genes, protecting cells from the consequences of mitochondrial DNA mutations (82). Mitofusins-1 and -2 are expressed in the lung (82). Their hydrophobic heptad repeats mediate tethering through a GTPase-dependent mechanism (82). Mitophospholipase D enhances fusion by generating the fusogenic lipid, phosphatidic acid (43).

Mitofusin-2 not only controls mitochondrial form and function (20, 28, 36, 43, 65, 81–83) but also regulates SMC proliferation (27, 28). Indeed, mitofusin-2 was originally named hyperplasia suppressor gene because it prevents SMC hyperplasia in injured arteries by causing cell-cycle arrest through inhibition of ERK/MAPK signaling (28). Impaired mitochondrial fusion also alters mitochondrial membrane potential ({Delta}{Psi}m) and respiration (27). Preliminary data presented here suggest that decreased mitofusin-2 contributes to disruption of mitochondrial fusion seen in PAH (20) (Fig. 3).


Figure 3
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  		Fig. 3. Disruption in mitochondrial fusion in PAH: A: confocal microscopy reveals impaired mitochondrial fusion and SOD2 downregulation in human PAH PASMCs. Electron microscopy shows that fawn-hooded rat (FHR) PASMCs have small dysmorphic mitochondria at 12 wk, before development of PAH reproduced from Ref. 20. B: confocal microscopy reveals a deficiency of mitofusin 2 (green) in FHR PASMCs. There is no difference in dynamin-related protein 1 (DRP1) between FHR and consomic PASMCs in this representative image, suggesting the abnormality in FHR is impaired fusion rather than enhanced fission. Note increased 4,6-diamidino-2-phenylindole-stained nuclei (blue) in FHR, reflecting the accelerated smooth muscle cell proliferation in FHR. C: portion of a DNA microarray showing changes in mitochondria-related genes in FHR pulmonary artery. Probe sets with hybridization changes ≥2.0x between FHR at 20 and 40 wk, and no concordant changes in age-matched control rats are shown. Note depression of SOD2 and mitofusin-2 (mfn2). Chromosome 1 genes are highlighted in red. Values shown as a heat map (Java TreeView). D: 48-h incubation in H2O2 reverses nuclear translocation of HIF-1{alpha} and restores Kv1.5 (red) in FHR PASMCs, consistent with the hypothesis that a loss of mitochondrial ROS production causes the FHR's abnormalities, reproduced from Ref. 20. iPAH, idiopathic PAH; BN1, consomic rat.

 
Mitochondrial ROS as Redox Signaling Molecules in O2 Sensing

Tissues in the homeostatic O2 sensing system (e.g., SMCs in the resistance pulmonary arteries, ductus arteriosus and fetoplacental arteries, and the carotid and neuroepithelial bodies) use a fairly well-conserved O2 sensor-effector unit to optimize O2 uptake/delivery (99). Cytochrome-based redox sensors monitor functions that, while tied to oxidative metabolism, are upstream from ATP production, such as the activity of the electron transport chain. They then generate redox signaling molecules (ROS and redox couples) that regulate the activity of O2-sensitive K+ channels. Teleologically, there is little value in ATP-sensing, because changes in high-energy phosphates occur only late with anoxia or severe ischemia (7).

The initial clue that mitochondria might serve as vascular O2 sensors came from the parallels in the cardiovascular responses to authentic hypoxia and inhibitors of the proximal electronic transport chain (ETC) (rotenone-complex I; antimycin-complex III) (78). These particular ETC inhibitors are unique in mimicking hypoxia, causing the opposing effects on pulmonary versus systemic arteries (constriction vs. dilatation) and activating the carotid body. The other class of agents that mimic hypoxia are reducing/oxidizing agents, which emulate hypoxia and normoxia, respectively (76).

A Mitochondrial O2 Sensor in HPV

In aerobic metabolism, electrons are passed down a redox-potential gradient in the ETC from donors (mitochondrial NADH and FADH) to molecular O2. At complex IV, cytochrome oxidase transfers the reducing equivalents to O2, creating water. This electron flux powers H+ ion extrusion, creating the proton-motive force responsible for the mitochondria's negative membrane potential (–{Delta}{Psi}m), the potential that powers ATP-synthase (26) (Fig. 2). Although the ETC strives to keep the series of single electron transfers localized, there are illicit side reactions between semiquinones and molecular O2, resulting in a creation of superoxide anion (2, 3, 6, 59). The mitochondrial ETC is the major source of H2O2 in the cell, most of which comes from the mitochondrial superoxide dismutase (SOD2), which rapidly converts superoxide anion produced at complexes I and III (3) to H2O2 (26). ROS account for ~3% of net electron flux. Hypoxic inhibition of normoxic ROS production is unique to pulmonary arteries (3, 5, 6, 9, 10, 20, 25, 61, 62, 68, 69, 75) and occurs within seconds of moderate hypoxia, before onset of HPV. In some cases, the ROS appear to originate from mitochondria (3); in other cases, from an NAD(P)H oxidoreductase (61, 62, 69). It is likely that both enzyme cascades produce ROS; however, HPV persists in the absence of the gp91phox containing NADPH oxidase (8). In most systemic arteries, ROS production is much lower than in the pulmonary arteries and is not inhibited by moderate hypoxia (38, 59). It is this unique ability to rapidly alter production of a diffusible ROS that allows PASMC mitochondria to control Kv channel function (3, 6).

H2O2, by virtue of its relatively nontoxic nature and moderate diffusion radius, serves as a signaling molecule communicating the PO2 (sensed in the mitochondria) to the plasma membrane (Kv channels) and transcription factors (10, 99). This mitochondrial-based O2 sensor is central to the mechanism of HPV (3, 10, 59, 95). Indeed, when pulmonary arteries lose this dynamic mitochondrial ROS generation, as occurs upon exposure to chronic hypoxia, HPV is depressed (53, 72, 75, 85). By regulating the gating of channels, such as Kv1.5, mitochondrial H2O2 determines PASMC membrane potential (11, 72, 76). During normoxia, mitochondria-derived H2O2 opens O2-sensitive Kv channel in PASMCs; conversely, in hypoxia ROS withdrawal inhibits these channels, depolarizing PASMC membrane potential, increasing Ca2+ influx and initiating HPV (59). Certain Kv channels are O2 sensitive (e.g., Kv1.5, Kv2.1, Kv3.1b, and Kv9.3), due in part to key sulfhydryl-containing amino acids (64). Although there is controversy regarding the vector of the effect of hypoxia on ROS (down vs. up; Refs. 49, 95, and 97; see recent debate; Refs. 94 and 98), both camps confirm a central role of the PASMC mitochondria as the source of signaling ROS (95–97).

Mitochondrial and Ion Channel Diversity

There is both ionic and mitochondrial diversity among arterial beds, which explains the localization of HPV (and perhaps PAH) to small pulmonary arteries (4, 11, 59). The mitochondria in resistance PASMCs are relatively unique in making a relatively large amount of ROS during normoxia and even more importantly this ROS production is rapidly inhibited by moderate hypoxia (20, 59). Likewise, these small arteries are enriched in O2-sensitive Kv channels (11). The renal artery, for example, lacks the hypoxia-inhibited mitochondrial ROS signal and dilates in response to hypoxia. PASMCs are also enriched in SOD2 (relative to renal arteries) (59), which serves both to create this redox signaling molecule and to neutralize more toxic superoxide anion, thereby protecting mitochondrial DNA. SOD2 activity is dynamically regulated within optimal ranges—the lower limit being sufficient to remove mitochondrial superoxide production, whereas the upper limit is kept low enough to avoid excess H2O2 production.

The Fawn-Hooded Rat

The common experimental models for creating PAH by exposing animals to monocrotaline (58), chronic hypoxia (73) [sometime augmented by the vascular endothelial growth factor (VEGF) receptor antagonist, SU5416 (80, 90)], do not fully mimic human PAH. Except for the latter model, the PAH models lack neointimal thickening, and none of the models displays plexiform lesions. Moreover, most models evolve rapidly (in 2 wk) in response to a single extrinsic toxic stimulus (monocrotaline, hypoxia, etc). The fawn-hooded rat (FHR), a mutant strain named for its brown mantle of fur, is unique in spontaneously developing PAH (42). FHR PAH is heritable (84) with high penetrance (42). FHR typically die of slowly evolving PAH at ~1 yr of age; notably PAH is absent until age 20 wk (20). FHR share additional similarities with human PAH, including enhanced vasoconstriction to serotonin, a platelet storage-pool deficiency (12), and exaggerated rates of PASMC proliferation. FHR are hypoxia sensitive, being prone to develop pulmonary hypertension and alveolar simplification (46, 47) when exposed to mild hypoxia, at levels that do not affect normal rodents (84).

We recently found that the FHR's PASMC mitochondria are dysmorphic, and the mitochondrial reticulum is fragmented before the onset of PAH (Fig. 3). The observed hyperpolarization of {Delta}{Psi}m and reduction in ROS production are mirrored in PASMCs from idiopathic PAH patients (20). In PAH, mitochondrial abnormalities that shift metabolism away from oxidative phosphorylation toward glycolysis (notably PDK activation) lead to a normoxic impairment of electron flux and reduced mitochondrial ROS production. This pseudohypoxic signal is associated with normoxic activation (nuclear translocation) of HIF-1{alpha}. HIF-1{alpha} activation appears to decrease expression of Kv1.5, and these abnormalities are reversed by either low-doses of exogenous H2O2 or a HIF-1{alpha} dominant-negative construct (20). The absence of PAH or mitochondrial dysfunction in consomic rats (FHR-BN1), which differ from FHR only in having a chromosome 1 introgressed from Brown Norway rats, indicates the initiating genes likely reside on chromosome 1. Using DNA microarrays, we identified a series of candidate genes that has biological plausibility to explain the mitochondria-ROS-HIF-Kv abnormalities, including SOD2 and HIF-3{alpha}, a HIF-1{alpha} repressor (20) (Fig. 3).

Decreased Kv expression is an emerging hallmark of the PAH PASMCs occurring in human PAH (20, 106) and all known experimental models (20, 55, 60, 75) [including those due to BMPR2 dysfunction (104) or excess SERT activity (37)]. Interestingly, Kv1.5 is inhibited by the anorexigens (70, 100) and by serotonin (30), and restoring Kv1.5 expression reduces experimental PAH (72). Decreased expression and function of PASMC Kv channels have two consequences that favor cell accumulation, leading to the proliferative obstructive vasculopathy. First, the depolarization resulting from the loss of Kv channels leads to Ca2+ overload that activates transcription factors that stimulate proliferation (notably NFAT) (21). Second, the loss of Kv channels leads to an accumulation of intracellular K+, which inhibits caspase, impairing apoptosis, rendering the artery unable to eliminate abnormal cells (32, 44, 55, 77). This abnormal mitochondrial-ROS-HIF-1{alpha}-Kv pathway is recapitulated in human cancers. Supporting the notion that PAH and cancer share similar mechanisms, mitochondrial therapy (inhibition of PDK) or Kv1.5 gene therapy partially regresses both PAH and cancer (19, 20, 72).

SOD2 and PAH?

SOD2 is a candidate tumor-suppressor gene, which supports the notion that SOD2 deficiency promotes cell proliferation (23, 48). Normally, SOD2 expression is induced or repressed to match ROS production (more ROS = more SOD2). This avoids damage to the ETC and mitochondrial DNA (26). Low SOD2 activity/expression in FHR occurs by mechanisms that are quite distinct from the deletion of alleles that creates SOD2+/– mice, mice that have an oxidative stress phenotype (103). In FHR, the low ROS levels result both from decreased SOD2 expression and from inhibition of electron entry to the ETC, due to excessive PDK activity. PDK inhibits pyruvate dehydrogenase activity, which limits Krebs' cycle activity (Fig. 2). This decreases delivery of reducing equivalents (NADH and FADH) to the ETC with a resulting reduction in ROS. In contrast, oxidative damage in SOD2 knockout mice likely occurs because the delivery of electrons to the ETC is unimpaired and yet they lack SOD2 and so have impaired capacity to dismutate a normal rate of superoxide radicals. The possibility that an inherited deficiency of SOD2 expression in PAH is mechanistically important is suggested by the localization of the SOD2 gene on FHR chromosome 1, early downregulation of SOD2 in FHR (before onset of PAH), and the discovery of a parallel SOD deficiency in human idiopathic PAH (20). It is unknown whether decreased SOD2 generation reflects epigenetic gene silencing or a response to the loss of ROS, which normally induce SOD2 transcription.

Therapeutic Implications

Dichloroacetate is a prototypical inhibitor of mitochondrial PDK. This agent has been safely used in children with inherited mitochondrial disorders and lactic acidosis (86, 87). Dichloroacetate restores oxidative metabolism in FHR PASMCs, shifting them away from the proliferative/apoptosis-resistant glycolytic state, while having no effects on normal cells (19, 20, 41, 86). These metabolic changes reverse the hypoxic phenotype of FHR, restoring the relatively depolarized {Delta}{Psi}m of PASMCs and increasing ROS production to normoxic levels. This reverses HIF-1{alpha} activation and restores Kv1.5 expression, thereby lowering cytosolic Ca2+ and reducing the severity and mortality of FHR/PAH (20). Dichloroacetate also causes regression of PAH induced by chronic hypoxia or monocrotaline (20, 55, 60). The same doses of dichloroacetate decrease tumor growth, in an athymic rat model of transplanted human lung cancer cells, by an identical mechanism (19). Given the preexisting safety data based on the use of dichloroacetate in humans and its dramatic effects in preclinical models, it is reasonable to proceed with the investigation of this agent in human subjects afflicted with PAH and cancer. We do not advocate the off-label use of the drug. More preclinical studies and, eventually, more carefully performed clinical trials are required to assess the potential therapeutic agents that seek to normalize the mitochondria-ROS-HIF-1{alpha}-Kv1.5 in PAH (e.g., PDK inhibitors, HIF-1{alpha} inhibitors, and Kv channel augmentation).

Conclusions

The mitochondria are important O2 sensors, and a disruption of the mitochondria ROS-HIF-Kv pathway contributes to both PAH and cancer. It is likely that this pathway can be therapeutically targeted to regress PAH and cancer.


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This work was supported by National Heart, Lung, and Blood Institute Grants HL-071115 (to S. L. Archer) and RO1-HL-65322 (to E. K. Weir).


   ACKNOWLEDGMENTS
 
The hypothesis that mitochondria are central to PAH and cancer reflects an intellectual partnership with Dr. Evangelos Michelakis. S. L. Archer holds a provisional patent for the use of dichloroacetate in treating cancer: Michelakis ED and Archer SL (2005) A method of treating cancer using dichloroacetate (Ref: 2004055 US Prov).


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. L. Archer, Univ. of Chicago, Sect. of Cardiology, MC 6080, 5841 S. Maryland Ave., Chicago, IL 60637 (e-mail: sarcher{at}medicine.bsd.uchicago.edu)


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  1. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research "Work in progress." Circulation 102: 2781–2791, 2000.[Abstract/Free Full Text]
  2. Archer SL, Hampl V, Nelson DP, Sidney E, Peterson DA, Weir EK. Dithionite increases radical formation and decreases vasoconstriction in the lung. Evidence that dithionite does not mimic alveolar hypoxia. Circ Res 77: 174–181, 1995.[Abstract/Free Full Text]
  3. Archer SL, Huang J, Henry T, Peterson D, Weir EK. A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 73: 1100–1112, 1993.[Abstract/Free Full Text]
  4. Archer SL, Huang JM, Reeve HL, Hampl V, Tolarova S, Michelakis E, Weir EK. Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res 78: 431–442, 1996.[Abstract/Free Full Text]
  5. Archer SL, Michelakis ED, Thebaud B, Bonnet S, Moudgil R, Wu XC, Weir EK. A central role for oxygen-sensitive K+ channels and mitochondria in the specialized oxygen-sensing system. Novartis Found Symp 272: 157–171, 2006.[Medline]
  6. Archer SL, Nelson DP, Weir EK. Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung. J Appl Physiol 67: 1903–1911, 1989.[Abstract/Free Full Text]
  7. Archer SL, Nelson DP, Zimmer S, From AH, Weir EK. Hypoxic pulmonary vasoconstriction is unaltered by creatine depletion induced by dietary beta-guanidino propionic acid. Life Sci 45: 1081–1088, 1989.[CrossRef][Web of Science][Medline]
  8. Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, Weir EK. O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci USA 96: 7944–7949, 1999.[Abstract/Free Full Text]
  9. Archer SL, Weir EK, Reeve HL, Michelakis E. Molecular identification of O2 sensors and O2-sensitive potassium channels in the pulmonary circulation. Adv Exp Med Biol 475: 219–240, 2000.[Web of Science][Medline]
  10. Archer SL, Will JA, Weir EK. Redox status in the control of pulmonary vascular tone. Herz 11: 127–141, 1986.[Web of Science][Medline]
  11. Archer SL, Wu XC, Thebaud B, Nsair A, Bonnet S, Tyrrell B, McMurtry MS, Hashimoto K, Harry G, Michelakis ED. Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction. Ionic diversity in smooth muscle cells. Circ Res 95: 308–318, 2004.[Abstract/Free Full Text]
  12. Ashmore RC, Rodman DM, Sato K, Webb SA, O'Brien RF, McMurtry IF, Stelzner TJ. Paradoxical constriction to platelets by arteries from rats with pulmonary hypertension. Am J Physiol Heart Circ Physiol 260: H1929–H1934, 1991.[Abstract/Free Full Text]
  13. Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG, Eng C, Latif F, Maher ER. Germline SDHD mutation in familial phaeochromocytoma. Lancet 357: 1181–1182, 2001.[CrossRef][Web of Science][Medline]
  14. Balabanian K, Foussat A, Dorfmuller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, Portier A, Marfaing-Koka A, Krzysiek R, Rimaniol AC, Simonneau G, Emilie D, Humbert M. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 165: 1419–1425, 2002.[Abstract/Free Full Text]
  15. Baloh RH. Mitochondrial dynamics and peripheral neuropathy. Neuroscientist (October 2, 2007); doi:10.1177/10738584073073.
  16. Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, Miyazono K, Li E, Bloch KD. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol 287: L1241–L1247, 2004.[Abstract/Free Full Text]
  17. Bereiter-Hahn J, Voth M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27: 198–219, 1994.[CrossRef][Web of Science][Medline]
  18. Boldogh IR, Pon LA. Mitochondria on the move. Trends Cell Biol 17: 502–510, 2007.[CrossRef][Web of Science][Medline]
  19. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11: 37–51, 2007.[CrossRef][Web of Science][Medline]
  20. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet SN, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir E, Archer SL. An abnormal mitochondrial-HIF-1-Kv channel pathway disrupts oxygen-sensing and triggers pulmonary arterial hypertension (PAH) in fawn-hooded rats: similarities to human PAH. Circulation 113: 2630–2641, 2006.[Abstract/Free Full Text]
  21. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 104: 11418–11423, 2007.[Abstract/Free Full Text]
  22. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 104: 11418–11423, 2007.[Abstract/Free Full Text]
  23. Bravard A, Sabatier L, Hoffschir F, Ricoul M, Luccioni C, Dutrillaux B. SOD2: a new type of tumor-suppressor gene? Int J Cancer 51: 476–480, 1992.[Web of Science][Medline]
  24. Bull TM, Golpon H, Hebbel RP, Solovey A, Cool CD, Tuder RM, Geraci MW, Voelkel NF. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost 90: 698–703, 2003.[Web of Science][Medline]
  25. Burke-Wolin T, Wolin MS. H2O2 and cGMP may function as an O2 sensor in the pulmonary artery. J Appl Physiol 66: 167–170, 1989.[Abstract/Free Full Text]
  26. Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29: 222–230, 2000.[CrossRef][Web of Science][Medline]
  27. Chen H, Chan DC. Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 14: R283–R289, 2005.[Abstract/Free Full Text]
  28. Chen KH, Guo X, Ma D, Guo Y, Li Q, Yang D, Li P, Qiu X, Wen S, Xiao RP, Tang J. Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol 6: 872–883, 2004.[CrossRef][Web of Science][Medline]
  29. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327: 70–75, 1992.[Abstract]
  30. Cogolludo A, Moreno L, Lodi F, Frazziano G, Cobeno L, Tamargo J, Perez-Vizcaino F. Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells: role of 5-HT2A receptors, caveolin-1, and KV15 channel internalization. Circ Res 98: 931–938, 2006.[Abstract/Free Full Text]
  31. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 105: 21–34, 2000.[Web of Science][Medline]
  32. Cowan KN, Leung WC, Mar C, Bhattacharjee R, Zhu Y, Rabinovitch M. Caspases from apoptotic myocytes degrade extracellular matrix: a novel remodeling paradigm. Faseb J 19: 1848–1850, 2005.
  33. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67: 737–744, 2000.[CrossRef][Web of Science][Medline]
  34. Frederick RL, Shaw JM. Moving mitochondria: establishing distribution of an essential organelle. Traffic 8: 1668–1675, 2007.[CrossRef][Web of Science][Medline]
  35. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168: 659–669, 2006.[Abstract/Free Full Text]
  36. Griffin EE, Detmer SA, Chan DC. Molecular mechanism of mitochondrial membrane fusion. Biochim Biophys Acta 1763: 482–489, 2006.[Medline]
  37. Guignabert C, Izikki M, Tu LI, Li Z, Zadigue P, Barlier-Mur AM, Hanoun N, Rodman D, Hamon M, Adnot S, Eddahibi S. Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res 98: 1323–1330, 2006.[Abstract/Free Full Text]
  38. Gupte SA, Kaminski PM, Floyd B, Agarwal R, Ali N, Ahmad M, Edwards J, Wolin MS. Cytosolic NADPH may regulate differences in basal Nox oxidase-derived superoxide generation in bovine coronary and pulmonary arteries. Am J Physiol Heart Circ Physiol 288: H13–H21, 2005.[Abstract/Free Full Text]
  39. Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 115: 1275–1284, 2007.[Abstract/Free Full Text]
  40. Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, Poubeau P, Cerrina J, Duroux P, Drouet L. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99: 249–254, 1995.[CrossRef][Web of Science][Medline]
  41. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66: 324–330, 2006.[Abstract/Free Full Text]
  42. Kentera D, Susic D, Veljkovic V, Tucakovic G, Koko V. Pulmonary artery pressure in rats with hereditary platelet function defect. Respiration 54: 110–114, 1988.[Web of Science][Medline]
  43. Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. Structural basis of mitochondrial tethering by mitofusin complexes. Science 305: 858–862, 2004.[Abstract/Free Full Text]
  44. Krick S, Platoshyn O, Sweeney M, Kim H, Yuan JX. Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol Cell Physiol 280: C970–C979, 2001.[Abstract/Free Full Text]
  45. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26: 81–84, 2000.[CrossRef][Web of Science][Medline]
  46. Le Cras TD, Kim DH, Gebb S, Markham NE, Shannon JM, Tuder RM, Abman SH. Abnormal lung growth and the development of pulmonary hypertension in the Fawn-Hooded rat. Am J Physiol Lung Cell Mol Physiol 277: L709–L718, 1999.[Abstract/Free Full Text]
  47. Le Cras TD, Kim DH, Markham NE, Abman AS. Early abnormalities of pulmonary vascular development in the Fawn-Hooded rat raised at Denver's altitude. Am J Physiol Lung Cell Mol Physiol 279: L283–L291, 2000.[Abstract/Free Full Text]
  48. Li N, Oberley TD, Oberley LW, Zhong W. Overexpression of manganese superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype. Prostate 35: 221–233, 1998.[CrossRef][Web of Science][Medline]
  49. Liu JQ, Sham JS, Shimoda LA, Kuppusamy P, Sylvester JT. Hypoxic constriction and reactive oxygen species in porcine distal pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 285: L322–L333, 2003.[Abstract/Free Full Text]
  50. Long L, MacLean MR, Jeffery TK, Morecroft I, Yang X, Rudarakanchana N, Southwood M, James V, Trembath RC, Morrell NW. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98: 818–827, 2006.[Abstract/Free Full Text]
  51. Marcos E, Fadel E, Sanchez O, Humbert M, Dartevelle P, Simonneau G, Hamon M, Adnot S, Eddahibi S. Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 94: 1263–1270, 2004.[Abstract/Free Full Text]
  52. Maynard MA, Qi H, Chung J, Lee EH, Kondo Y, Hara S, Conaway RC, Conaway JW, Ohh M. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 278: 11032–11040, 2003.[Abstract/Free Full Text]
  53. McMurtry IF, Petrun MD, Reeves JT. Lungs from chronically hypoxic rats have decreased pressor response to acute hypoxia. Am J Physiol Heart Circ Physiol 235: H104–H109, 1978.[Abstract/Free Full Text]
  54. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 115: 1479–1491, 2005.[CrossRef][Web of Science][Medline]
  55. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95: 830–840, 2004.[Abstract/Free Full Text]
  56. McMurtry MS, Moudgil R, Hashimoto K, Bonnet S, Michelakis ED, Archer SL. Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 292: L872–L878, 2007.[Abstract/Free Full Text]
  57. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112: 423–431, 2005.[Abstract/Free Full Text]
  58. Meyrick B, Gamble W, Reid L. Development of Crotalaria pulmonary hypertension: hemodynamic and structural study. Am J Physiol Heart Circ Physiol 239: H692–H702, 1980.[Abstract/Free Full Text]
  59. Michelakis ED, Hampl V, Nsair A, Wu X, Harry G, Haromy A, Gurtu R, Archer SL. Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res 90: 1307–1315, 2002.[Abstract/Free Full Text]
  60. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105: 244–250, 2002.[Abstract/Free Full Text]
  61. Mohazzab KM, Wolin MS. Properties of a superoxide anion-generating microsomal NADH oxidoreductase, a potential pulmonary artery PO2 sensor. Am J Physiol Lung Cell Mol Physiol 267: L823–L831, 1994.[Abstract/Free Full Text]
  62. Mohazzab KM, Wolin MS. Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol Lung Cell Mol Physiol 267: L815–L822, 1994.[Abstract/Free Full Text]
  63. Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 104: 790–795, 2001.[Abstract/Free Full Text]
  64. Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol 98: 390–403, 2005.[Abstract/Free Full Text]
  65. Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H. Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 280: 25060–25070, 2005.[Abstract/Free Full Text]
  66. Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, Coccolo F, Ventura C, Phillips JA, 3rd Knowles JA, Janssen B, Eickelberg O, Eddahibi S, Herve P, Nichols WC, Elliott G. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol 43: 33S–39S, 2004.[Abstract/Free Full Text]
  67. Nunes H, Humbert M, Sitbon O, Morse JH, Deng Z, Knowles JA, Le Gall C, Parent F, Garcia G, Herve P, Barst RJ, Simonneau G. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 167: 1433–1439, 2003.[Abstract/Free Full Text]
  68. Omar HA, Mohazzab KM, Mortelliti MP, Wolin MS. O2-dependent modulation of calf pulmonary artery tone by lactate: potential role of H2O2 and cGMP. Am J Physiol Lung Cell Mol Physiol 264: L141–L145, 1993.[Abstract/Free Full Text]
  69. Paky A, Michael JR, Burke-Wolin TM, Wolin MS, Gurtner GH. Endogenous production of superoxide by rabbit lungs: effects of hypoxia or metabolic inhibitors. J Appl Physiol 74: 2868–2874, 1993.[Abstract/Free Full Text]
  70. Perchenet L, Hilfiger L, Mizrahi J, Clement-Chomienne O. Effects of anorexinogen agents on cloned voltage-gated K+ channel hKv15. J Pharmacol Exp Ther 298: 1108–1119, 2001.[Abstract/Free Full Text]
  71. Pope JE, Lee P, Baron M, Dunne J, Smith D, Docherty PS, Bookman A, Abu-Hakima M. Prevalence of elevated pulmonary arterial pressures measured by echocardiography in a multicenter study of patients with systemic sclerosis. J Rheumatol 32: 1273–1278, 2005.[Abstract/Free Full Text]
  72. Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G, Sultanian R, Koshal A, Archer SL. In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107: 2037–2044, 2003.[Abstract/Free Full Text]
  73. Rabinovitch M, Gamble W, Nadas AS, Miettinen OS, Reid L. Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. Am J Physiol Heart Circ Physiol 236: H818–H827, 1979.[Abstract/Free Full Text]
  74. Raoul W, Wagner-Ballon O, Saber G, Hulin A, Marcos E, Giraudier S, Vainchenker W, Adnot S, Eddahibi S, Maitre B. Effects of bone marrow-derived cells on monocrotaline- and hypoxia-induced pulmonary hypertension in mice. Respir Res 8: 8, 2007.[CrossRef][Medline]
  75. Reeve HL, Michelakis E, Nelson DP, Weir EK, Archer SL. Alterations in a redox oxygen sensing mechanism in chronic hypoxia. J Appl Physiol 90: 2249–2256, 2001.[Abstract/Free Full Text]
  76. Reeve HL, Weir EK, Nelson DP, Peterson DA, Archer SL. Opposing effects of oxidants and antioxidants on K+ channel activity and tone in rat vascular tissue. Exp Physiol 80: 825–834, 1995.[Abstract]
  77. Remillard CV, Yuan JX. Activation of K+ channels: an essential pathway in programmed cell death. Am J Physiol Lung Cell Mol Physiol 286: L49–L67, 2004.[Abstract/Free Full Text]
  78. Rounds S, McMurtry IF. Inhibitors of oxidative ATP production cause transient vasoconstriction and block subsequent pressor responses in rat lungs. Circ Res 48: 393–400, 1981.[Abstract/Free Full Text]
  79. Sahara M, Sata M, Morita T, Nakamura K, Hirata Y, Nagai R. Diverse contribution of bone marrow-derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation 115: 509–517, 2007.[Abstract/Free Full Text]
  80. Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. Faseb J 19: 1178–1180, 2005.[Abstract/Free Full Text]
  81. Santel A. Get the balance right: mitofusins roles in health and disease. Biochim Biophys Acta 1763: 490–499, 2006.[Medline]
  82. Santel A, Frank S, Gaume B, Herrler M, Youle RJ, Fuller MT. Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci 116: 2763–2774, 2003.[Abstract/Free Full Text]
  83. Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114: 867–874, 2001.[Abstract]
  84. Sato K, Webb S, Tucker A, Rabinovitch M, O'Brien RF, McMurtry IF, Stelzner TJ. Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. Am Rev Respir Dis 145: 793–797, 1992.[Web of Science][Medline]
  85. Smirnov SV, Robertson TP, Ward JPT, Aaronson PI. Chronic hypoxia is associated with reduced delayed rectifier K+ current in rat pulmonary artery muscle cells. Am J Physiol Heart Circ Physiol 266: H365–H370, 1994.[Abstract/Free Full Text]
  86. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, Hutson AD, Neiberger RE, O'Brien RG, Perkins LA, Quisling RG, Shroads AL, Shuster JJ, Silverstein JH, Theriaque DW, Valenstein E. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117: 1519–1531, 2006.[Abstract/Free Full Text]
  87. Stacpoole PW, Owen R, Flotte TR. The pyruvate dehydrogenase complex as a target for gene therapy. Curr Gene Ther 3: 239–245, 2003.[CrossRef][Medline]
  88. Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC, Bevan JA, Fishman MC, Zapol WM. Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res 81: 34–41, 1997.[Abstract/Free Full Text]
  89. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 114: 464–469, 1991.[Abstract/Free Full Text]
  90. Taraseviciene-Stewart L, Gera L, Hirth P, Voelkel NF, Tuder RM, Stewart JM. A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model. Can J Physiol Pharmacol 80: 269–274, 2002.[CrossRef][Web of Science][Medline]
  91. Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J 30: 1103–1110, 2007.[Abstract/Free Full Text]
  92. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 114: 225S–230S, 1998.[CrossRef][Web of Science][Medline]
  93. Warburg O. Uber den Stoffwechsel der Tumoren. Berlin: Julius Springer, 1926.
  94. Ward JP. Point: Hypoxic pulmonary vasoconstriction is mediated by increased production of reactive oxygen species. J Appl Physiol 101: 993–995, 2006.[Free Full Text]
  95. Waypa GB, Chandel NS, Schumacker PT. Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res 88: 1259–1266, 2001.[Abstract/Free Full Text]
  96. Waypa GB, Marks JD, Mack MM, Boriboun C, Mungai PT, Schumacker PT. Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ Res 91: 719–726, 2002.[Abstract/Free Full Text]
  97. Waypa GB, Schumacker PT. O2 sensing in hypoxic pulmonary vasoconstriction: the mitochondrial door re-opens. Respir Physiol Neurobiol 132: 81–91, 2002.[CrossRef][Web of Science][Medline]
  98. Weir EK, Archer SL. Counterpoint: Hypoxic pulmonary vasoconstriction is not mediated by increased production of reactive oxygen species. J Appl Physiol 101: 995–998, 2006.[Free Full Text]
  99. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 353: 2042–2055, 2005.[Free Full Text]
  100. Weir EK, Reeve HL, Huang JM, Michelakis E, Nelson DP, Hampl V, Archer SL. Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 94: 2216–2220, 1996.[Abstract/Free Full Text]
  101. West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, Rodman DM. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94: 1109–1114, 2004.[Abstract/Free Full Text]
  102. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 52: 2125–2132, 2005.[CrossRef][Web of Science][Medline]
  103. Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A. Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 273: 28510–28515, 1998.[Abstract/Free Full Text]
  104. Young KA, Ivester C, West J, Carr M, Rodman DM. BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 290: L841–L848, 2006.[Abstract/Free Full Text]
  105. Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JX. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci USA 101: 13861–13866, 2004.[Abstract/Free Full Text]
  106. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98: 1400–1406, 1998.[Abstract/Free Full Text]
  107. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285: L740–L754, 2003.[Abstract/Free Full Text]
  108. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 96: 442–450, 2005.[Abstract/Free Full Text]



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