Update on Pulmonary Hypertension 2009

Gladwin, Mark T.; Ghofrani, Hossein Ardeschir

doi:10.1164/rccm.201002-0235up

Cited by 18 publications

(18 citation statements)

References 49 publications

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“…It afflicts approximately 100,000 individuals and causes 20,000 deaths annually in the United States [4]. PAH is characterized by an excessive proliferation of the Pulmonary Artery Smooth Muscle Cells (PASMCs), the diseased Pulmonary Arteries (PA) in PAH are characterized by vasoconstriction, suppressed apoptosis and increased proliferation within the vascular wall [5], [6].…”

Section: Introductionmentioning

confidence: 99%

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

et al. 2012

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IntroductionPulmonary Arterial Hypertension (PAH) is a progressively devastating disease characterized by excessive proliferation of the Pulmonary Arterial Smooth Muscle Cells (PASMCs). Studies suggest that PAH and cancers share an apoptosis-resistant state featuring excessive cell proliferation. The proliferation of cancer cells is mediated by increased expression of Enhancer of Zeste Homolog 2 (EZH2), a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes. However, the role of EZH2 in PAH has not been studied. In this study, it is hypothesized that EZH2 could play a role in the proliferation of PASMCs.MethodsIn the present study, the expression patterns of EZH2 were investigated in normal and hypertensive mouse PASMCs. The effects of EZH2 overexpression on the proliferation of human PASMCs were tested. PASMCs were transfected with EZH2 or GFP using nucleofector system. After transfection, the cells were incubated for 48 hours at 37°C. Proliferation and cell cycle analysis were performed using flow cytometry. Apoptosis of PASMCs was determined using annexin V staining and cell migration was tested by wound healing assay.ResultsEZH2 protein expression in mouse PASMCs were correlated with an increase in right ventricular systolic pressure and Right Ventricular Hypertrophy (RVH). The overexpression of EZH2 in human PASMCs enhances proliferation, migration, and decrease in the rate of apoptosis when compared to GFP-transfected cells. In the G2/M phase of the EZH2 transfected cells, there was a 3.5 fold increase in proliferation, while there was a significant decrease in the rate of apoptosis of PASMCs, when compared to control.ConclusionThese findings suggest that EZH2 plays a role in the migration and proliferation of PASMCs, which is a major hallmark in PAH. It also suggests that EZH2 could play a role in the development of PAH and can serve as a potential target for new therapies for PAH.

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Section: Introductionmentioning

confidence: 99%

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

et al. 2012

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“…The approved uses of these medications have been extensively covered in other reviews and will not be fully addressed herein (55,56,82,99,108,110,111,117,119,120,123,126,259,260,360). There is a significant effort to develop new drugs that extend the utility of these therapies or have improved pharmacokinetics for particular uses.…”

Section: A Current and Emerging Clinical Uses Of Phosphodiesterase Imentioning

confidence: 99%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

552

546

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The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

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“…Under normal physiologic circumstances, NO is a vasodilator of deoxygenated tissue beds and serves to inhibit PLT‐mediated vascular thrombosis. NO is active in the pulmonary artery vasculature (which is deoxygenated) and this bed is particularly susceptible to depletion of NO—a finding that may link chronic hemolysis to pulmonary hypertension 12 . The renal vascular bed also appears to be sensitive to NO depletion.…”

Section: Nomentioning

confidence: 99%

The air we breathe: three vital respiratory gases and the red blood cell: oxygen, nitric oxide, and carbon dioxide

Dzik

2011

Transfusion

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Three vital respiratory gases-oxygen (O(2)), nitric oxide (NO), and carbon dioxide (CO(2))-intersect at the level of the human red blood cell (RBC). In addition to hemoglobin (Hb)'s central role in O(2) transport, interaction of Hb with the Band 3 metabolon balances RBC energy flow. 2,3-Diphosphoglycerate enhances O(2) transport across the placenta and plays an important role in regulating RBC plasticity. NO is a key mediator of hypoxic vasodilation, but the precise role of RBC Hb remains controversial. In addition to established theories that depend on RBC uptake, delivery, and discharge of NO or its metabolites, an alternative hypothesis based on RBC permeability is suggested. NO depletion by free Hb may account for several clinical features seen during intravascular hemolysis or during deliberate infusion of Hb solutions used as RBC substitutes. CO(2) released by tissues triggers oxygen release through a series of well-coordinated reactions centered on the Band 3 metabolon. While RBC carbonic anhydrase and the Band 3 anion exchanger are central to this process, there is surprisingly little research on the kinetics of CO(2) clearance by transfusion. The three RBC gases are directly related to the three principal gases of Earth's atmosphere. Human fossil fuel consumption dumps 90 million metric tons of carbon into the atmosphere annually. Increasing CO(2) levels are linked to global warming, melting Arctic ice, rising sea levels, and climate instability. Just as individual cells depend on balance of the three vital gases, so too will their balance determine survival of life on Earth.

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Update on Pulmonary Hypertension 2009

Cited by 18 publications

References 49 publications

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

The air we breathe: three vital respiratory gases and the red blood cell: oxygen, nitric oxide, and carbon dioxide

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