Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats

Michelakis, Evangelos D.; McMurtry, M. Sean; Wu, Xi Chen; Dyck, Jason R.B.; Moudgil, Rohit; Hopkins, Teresa A.; Lopaschuk, Gary D.; Puttagunta, Lakshmi; Waite, Ross; Archer, Stephen L.

doi:10.1161/hc0202.101974

Cited by 338 publications

(283 citation statements)

References 31 publications

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“…1g). Since emerging evidence indicate that activation of mitochondrial signalling can affect HIF-1α stabilisation, we tested the efficacy of a pyruvate dehydrogenase kinase inhibitor DCA [26,27] (fig. 1f) to normalise the endothelial-derived Ob production using primary human P-ECs derived from control lung specimens.…”

Section: Resultsmentioning

confidence: 99%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH ( pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. @ERSpublications Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and antiinflammatory strategies in PH http://ow.ly/I00jh

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Section: Resultsmentioning

confidence: 99%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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“…Similarly, Fawn Hooded rats, a spontaneously pulmonary hypertensive rodent strain, have dysmorphic mitochondria with reduced expression of electron transport chain components. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, prevents and reverses the pulmonary hypertension of Fawn Hooded rats, indicating a pathogenetic relation between mitochondria function and pulmonary hypertension (24,25). Given these data and the low NO state of IPAH, we hypothesized that abnormalities of cellular metabolic energy pathways would be present in IPAH patients.…”

Section: Idiopathic Pulmonary Arterial Hypertension (Ipah) Is Pathogementioning

confidence: 99%

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Koeck

Lara

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

358

402

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Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NOcellular respiration ͉ nitric oxide ͉ oxygen consumption ͉ pulmonary hypertension ͉ mitochondrion I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease of unknown etiology characterized by a progressive increase in pulmonary artery pressure and vascular growth (1, 2). Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH. Abnormalities in vasodilators, specifically nitric oxide (NO), have been implicated in the pathogenesis of pulmonary hypertension (1-5). NO is produced in the lung by NO synthases (NOS; EC 1.14.13.39) (6-8). There is conclusive evidence from animal models of pulmonary hypertension, mice genetically deficient in endothelial NOS (eNOS), and complementation studies with gene transfer of NOSs for the concept that NO is a critical determinant of pulmonary vascular tone (6, 7, 9). Furthermore, pulmonary and total body NO are lower in IPAH patients as compared with healthy controls (3,(10)(11)(12), and the decrease of NO has been linked to increased arginase II and decreased eNOS expression in IPAH pulmonary endothelial cells in vivo (10,13).In addition to effects on vascular tone, NO regulates cellular bioenergetics through effects on glycolysis, oxygen consumption by mitochondrion, and mitochondrial biogenesis (14-17). For example, eNOS-deficient mice, which have mild pulmonary hypertension under normoxia and an exaggerated pulmonary vasoconstrictive response to hypoxia (18), have reduced mitochondria content in a wide range of tissues in association with significantly lower oxygen consumption and ATP content (14-17). Mitochondria are essential to cellular energy production in all higher organisms adapted to an oxygen-containing environment, i.e., ATP produced through oxidative phosphorylation. The electrochemical gradient used by mitochondrial F 0 F 1 ATP synthase to synthesize ATP from ADP is generated by the proton pump action performed by Complexes I, III, and IV of the respiratory chain. The proton pumping is accompanied by electron shuttling, whereby Complexes I and II, along with the flavoprotein-ubiquinone oxidoreductase, transfer electrons from different sources to ubiquinone (coenzyme Q). The electrons are then transferred sequentially to Complex III, cytochrome c, Complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain (I-IV) are located in the mitochondrial inner membrane. Thus, mitochondria are the primary oxygen demand in the body, accounting for Ϸ90% of cellular oxygen consumption. Conversely, under limiting oxygen conditions, cells turn to glycolysis to generate energy. In endothelial cells, ATP is generated nearly equivalently by glycolysis and cellular respiration (19), accounting for a relative tolerance ...

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“…Freshly dispersed PASMCs were studied with whole-cell patch clamping, as previously described. 6 PASMCs were superfused with extracellular fluid containing sildenafil or sildenafil plus the selective BK Ca inhibitor iberiotoxin. The effects of sildenafil on PA tone were assessed in phenylephrine (10 Ϫ5 mol/L)-preconstricted human PA rings (optimal resting tension 1 g).…”

Section: Michelakis Et Al Oral Sildenafil As Alternative Treatment Fomentioning

confidence: 99%

Long-Term Treatment With Oral Sildenafil Is Safe and Improves Functional Capacity and Hemodynamics in Patients With Pulmonary Arterial Hypertension

et al. 2003

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Background-The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown. Methods and Results-We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by Ն1 class in all patients. Pretreatment versus posttreatment values (meanϮSEM) were as follows: 6-minute walk, 376Ϯ30 versus 504Ϯ27 m, PϽ0.0001; mean PA pressure, 70Ϯ3 versus 52Ϯ3 mm Hg, PϽ0.007; pulmonary vascular resistance index 1702Ϯ151 versus 996Ϯ92 dyne · s · cm Ϫ5 · m Ϫ2, PϽ0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels. Figure 1. Short-term inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in PAH, 4,5 but ambulatory delivery in humans is cumbersome. Another strategy is to prolong the survival of cGMP in PASMCs by inhibiting type-5 phosphodiesterase (PD-5), an isoform that is primarily located in the penis and lungs, which rapidly degrades cGMP. Because of PD-5's tissue distribution (pulmonaryϾsystemic vasculature), PD-5 inhibitors are attractive candidate pulmonary vasodilators that minimally decrease systemic blood pressure. (75 mg) is an effective and relatively selective pulmonary vasodilator. 4,5 We hypothesized that PD-5 inhibition acutely causes human PA dilatation, in part by opening of BK Ca channels, and that it chronically improves hemodynamics and functional capacity in moderately severe PAH. Conclusion-This MethodsWe studied 5 consecutive patients with PAH (nϭ4 New York Heart Association [NYHA] class III; patient 3 class II). All subjects provided informed consent. Patients with class IV PAH were excluded because they often require epoprostenol, which could confound the assessment of sildenafil's effects. All the patients had been stable for Ͼ3 months, and their standard therapy was not altered before initiation of sildenafil. All were on diuretics and coumadin, and patients 2 and 4 were on Ca 2ϩ channel blockers because they had been shown to respond to iNO with Ͼ20% decrease in pulmonary vascular resistance (Figure 2). No patient was taking nitrates. All patients had primary pulmonary hypertension (PPH) except patient 2, w...

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Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats

Cited by 338 publications

References 31 publications

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Long-Term Treatment With Oral Sildenafil Is Safe and Improves Functional Capacity and Hemodynamics in Patients With Pulmonary Arterial Hypertension

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