Chronic obstructive pulmonary disease (COPD) is a major cause of chronic mortality. The objective of this study was to investigate the therapeutic potential of a novel potent histone deacetylase (HDAC) inhibitor MPT0E028 on emphysema.

A mouse model of porcine pancreatic elastase (PPE)-induced emphysema was orally administered 0, 25, or 50 mg/kg body weight (BW) of the MPT0E028 five times/week for 3 weeks. Pulmonary function, mean linear intercept (MLI), chest CT, inflammation, yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), surfactant protein C (SPC), T1-α, p53, and sirtuin 1 (SIRT1) levels were examined.

50 mg/kg BW of the MPT0E028 significantly decreased the tidal volume in emphysematous mice (p < 0.05). Emphysema severity was significantly reduced from 26.65% (PPE only) to 13.83% (50 mg/kg BW of the MPT0E028). Total cell counts, neutrophils, lymphocytes, and eosinophils significantly decreased with both 25 and 50 mg/kg BW of the MPT0E028 (p < 0.05). Also, 50 mg/kg BW of the MPT0E028 significantly decreased the levels of KC, TNF-α, and IL-6 in lung tissues and serum (p < 0.05). Expressions of p-TAZ/TAZ in lung tissues significantly decreased with 50 mg/kg BW of the MPT0E028 (p < 0.05). Expressions of p53 significantly decreased in alveolar regions with 50 mg/kg BW of the MPT0E028 (p < 0.05), and the expression of SPC increased in alveolar regions with 50 mg/kg BW of the MPT0E028 (p < 0.05).

Our study showed that the potent HDAC inhibitor MPT0E028 reduced the severity and inflammation of emphysema with improvement in lung function, which could be regulated by Hippo signaling pathway. The MPT0E028 may have therapeutic potential for emphysema.

• Ministry of Science and Technology, Taiwan

• alveolar epithelium
• alveolar type II cells
• emphysema
• lung
• oxidative stress
• tissue homeostasis

The roles of endogenous nitric oxide (NO) derived from the entire NO synthases (NOSs) system have yet to be fully elucidated. We addressed this issue in mice in which all three NOS isoforms were deleted. Under basal conditions, the triple n/i/eNOSs^−/− mice displayed significantly longer mean alveolar linear intercept length, increased alveolar destructive index, reduced lung elastic fiber content, lower lung field computed tomographic value, and greater end-expiratory lung volume as compared with wild-type (WT) mice. None of single NOS^−/− or double NOSs^−/− genotypes showed such features. These findings were observed in the triple n/i/eNOSs^−/− mice as early as 4 weeks after birth. Cyclopaedic and quantitative comparisons of mRNA expression levels between the lungs of WT and triple n/i/eNOSs^−/− mice by cap analysis of gene expression (CAGE) revealed that mRNA expression levels of three Wnt ligands and ten Wnt/β-catenin signaling components were significantly reduced in the lungs of triple n/i/eNOSs^−/− mice. These results provide the first direct evidence that complete disruption of all three NOS genes results in spontaneous pulmonary emphysema in juvenile mice in vivo possibly through down-regulation of the Wnt/β-catenin signaling pathway, demonstrating a novel preventive role of the endogenous NO/NOS system in the occurrence of pulmonary emphysema.

Atherosclerosis (AS), the most common underlying pathology for coronary artery disease, is a chronic inflammatory, proliferative disease in large- and medium-sized arteries. The vascular endothelium is important for maintaining vascular health. Endothelial dysfunction is a critical early event leading to AS, which is a major risk factor for stroke and myocardial infarction. Accumulating evidence has suggested the critical roles of histone deacetylases (HDACs) in regulating vascular cell homeostasis and AS. The purpose of this review is to present an updated view on the roles of HDACs (Class I, Class II, Class IV) and HDAC inhibitors in vascular dysfunction and AS. We also elaborate on the novel therapeutic targets and agents in atherosclerotic cardiovascular diseases.

• HDAC inhibitors
• atherosclerosis
• endothelial dysfunction
• epigenetic
• histone deacetylation
• macrophage
• smooth muscle cells

Although mutations in several genes have been reported in pulmonary arterial hypertension (PAH), most of PAH cases do not carry these mutations. This study aimed to identify a novel cause of PAH. To determine the disease-causing variants, direct sequencing and multiplex ligation-dependent probe amplification were performed to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, no disease-causing variants were found in any of BMPR2, ACVRL1, ENG, SMAD1/4/8, BMPR1B, NOTCH3, CAV1, or KCNK3. In this family, a female proband and her paternal aunt developed PAH in their childhood. Whole-exome next-generation sequencing was performed in the 2 PAH patients and the proband’s healthy mother, and a BRCA1-associated protein (BRAP) gene variant, p.Arg554Leu, was identified in the 2 family members with PAH, but not in the proband’s mother without PAH. Functional analyses were performed using human pulmonary arterial smooth muscle cells (hPASMCs). Knockdown of BRAP via small interfering RNA in hPASMCs induced p53 signaling pathway activation and decreased cell proliferation. Overexpression of either wild-type BRAP or p.Arg554Leu-BRAP cDNA constructs caused cell death confounding these studies, however we observed higher levels of p53 signaling inactivation and hPASMC proliferation in cells expressing p.Arg554Leu-BRAP compared to wild-type BRAP. In addition, p.Arg554Leu-BRAP induced decreased apoptosis of hPASMCs compared with wild-type BRAP. In conclusion, we have identified a novel variant of BRAP in a Japanese family with PAH and our results suggest it could have a gain-of-function. This study sheds light on new mechanism of PAH pathogenesis.

• Adolescent
• Adult
• Apoptosis
• Cells, Cultured
• Child
• Child, Preschool
• Exome/genetics
• Familial Primary Pulmonary Hypertension/genetics
• Familial Primary Pulmonary Hypertension/pathology
• Female
• Humans
• Infant
• Male
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/pathology
• Mutation
• Pedigree
• Pulmonary Artery/metabolism
• Pulmonary Artery/pathology
• Signal Transduction
• Ubiquitin-Protein Ligases/genetics
• Exome Sequencing
• Young Adult

• JSPS KAKENHI Grant

• DNA damage
• HDAC2
• cigarette smoke
• inflammation

Abnormal apoptosis of lung endothelial cells has been observed in emphysematous lung tissue and has been suggested to be an important upstream event in the pathogenesis of chronic obstructive pulmonary disease (COPD). Studies have shown that microRNAs (miRNAs) contribute to the pathogenesis of pulmonary diseases by regulating cell apoptosis. The present study was designed to investigate the expression of microRNA-34a (miR-34a) in human pulmonary microvascular endothelial cells (HPMECs) exposed to cigarette smoke extract (CSE), and the potential regulatory role of miR-34a in endothelial cell apoptosis.

Our results showed that the expression of miR-34a was significantly increased in CSE-treated HPMECs, and inhibiting miR-34a attenuated CSE-induced HPMEC apoptosis. Furthermore, expression of Notch-1, a receptor protein in the Notch signalling pathway, was decreased and was inversely correlated with miR-34a expression in HPMECs treated with CSE. Computational miRNA target prediction confirmed that Notch-1 is a target of miR-34a. Luciferase reporter assay further confirmed the direct interaction between miR-34a and the 3’-untranslated region (UTR) of Notch-1. Restoration of Notch-1 pathway was able to partially block the effect of miR-34a on HPMEC apoptosis. These results indicate that Notch-1 is a critical downstream target of miR-34a in regulating the CSE-induced HPMEC apoptosis.

Our results suggest that miR-34a plays a key role in CSE-induced endothelial cell apoptosis by directly regulating its target gene Notch-1 in endothelial cells.

• Apoptosis
• Cigarette smoke extract
• Notch-1
• Vascular endothelial cells
• miR-34a

Trichostatin A (TSA) is an anticancer drug that inhibits histone deacetylases (HDACs). Hypoxia-inducible factor 1 (HIF-1) participates in tumor angiogenesis by upregulating target genes, such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether TSA treatment increases HIF-1α stabilization via acetylation under normoxic conditions, which would lead to VEGF upregulation and resistance to anticancer drugs. TSA enhanced total HIF-1α and VEGF-HRE reporter activity under normoxic conditions. When cells were transfected with GFP-HIF-1α, treatment with TSA increased the number of green fluorescence protein (GFP)-positive cells. TSA also enhanced the nuclear translocation of HIF-1α protein, as assessed by immunoblotting and as evidenced by increased nuclear localization of GFP-HIF-1α. An increase in the interaction between HIF-1α and the VEGF promoter, which was assessed by a chromatin immunoprecipitation (ChIP) assay, led to activation of the VEGF promoter. TSA acetylated HIF-1α at lysine (K) 674, which led to an increase in TSA-induced VEGF-HRE reporter activity. In addition, TSA-mediated cell death was reduced by the overexpression of HIF-1α but it was rescued by transfection with a HIF-1α mutant (K674R). These data demonstrate that HIF-1α may be stabilized and translocated into the nucleus for the activation of VEGF promoter by TSA-mediated acetylation at K674 under normoxic conditions. These findings suggest that HIF-1α acetylation may lead to resistance to anticancer therapeutics, such as HDAC inhibitors, including TSA.

• HIF-1α
• acetylation
• drug-resistance
• normoxic conditions
• trichostatin A

• Caffeic acid
• Cell death
• Chelation
• Emphysema
• Hypoxia-inducible factor (HIF)
• Vascular endothelial growth factor (VEGF)

Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono- and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.

• autophagy
• caveolae endocytosis pathway
• cell death
• doxorubicin
• reactive oxygen species
• valproic acid

Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34⁺ progenitor cells to examine whether these genes are associated with COPD development.

This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34⁺ progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR.

The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells.

Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.

• Sirt1
• miR-126
• miR-34a
• p53

In patients with emphysema, invasive mechanical ventilation settings should be adjusted to minimize hyperinflation while reducing respiratory effort and providing adequate gas exchange. We evaluated the impact of pressure-controlled ventilation (PCV) and pressure support ventilation (PSV) on pulmonary and diaphragmatic damage, as well as cardiac function, in experimental emphysema.

Emphysema was induced by intratracheal instillation of porcine pancreatic elastase in Wistar rats, once weekly for 4 weeks. Control animals received saline under the same protocol. Eight weeks after first instillation, control and emphysema rats were randomly assigned to PCV (n = 6/each) or PSV (n = 6/each) under protective tidal volume (6 ml/kg) for 4 h. Non-ventilated control and emphysema animals (n = 6/group) were used to characterize the model and for molecular biology analysis. Cardiorespiratory function, lung histology, diaphragm ultrastructure alterations, extracellular matrix organization, diaphragmatic proteolysis, and biological markers associated with pulmonary inflammation, alveolar stretch, and epithelial and endothelial cell damage were assessed.

Emphysema animals exhibited cardiorespiratory changes that resemble human emphysema, such as increased areas of lung hyperinflation, pulmonary amphiregulin expression, and diaphragmatic injury. In emphysema animals, PSV compared to PCV yielded: no changes in gas exchange; decreased mean transpulmonary pressure (Pmean,L), ratio between inspiratory and total time (Ti/Ttot), lung hyperinflation, and amphiregulin expression in lung; increased ratio of pulmonary artery acceleration time to pulmonary artery ejection time, suggesting reduced right ventricular afterload; and increased ultrastructural damage to the diaphragm. Amphiregulin correlated with Pmean,L (r = 0.99, p < 0.0001) and hyperinflation (r = 0.70, p = 0.043), whereas Ti/Ttot correlated with hyperinflation (r = 0.81, p = 0.002) and Pmean,L (r = 0.60, p = 0.04).

In the model of elastase-induced emphysema used herein, PSV reduced lung damage and improved cardiac function when compared to PCV, but worsened diaphragmatic injury.

The online version of this article (doi:10.1186/s40635-016-0107-0) contains supplementary material, which is available to authorized users.

• Amphiregulin
• Diaphragm
• Echocardiography
• Emphysema
• Pressure support ventilation

• alveolar formation
• bronchopulmonary dysplasia
• emphysema
• lung homeostasis
• lung repair and regeneration

• VEGF
• alveolar septal cell death
• emphysema
• mTOR
• mammalian target of rapamycin
• oxidative stress
• proteinases
• vascular endothelial growth factor

• Animals
• Antigen-Presenting Cells/immunology
• Antigen-Presenting Cells/metabolism
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Disease Models, Animal
• Emphysema/etiology
• Emphysema/immunology
• Emphysema/metabolism
• Histone Deacetylases/metabolism
• Humans
• Lung/immunology
• Lung/metabolism
• Lung/pathology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs/genetics
• MicroRNAs/metabolism
• NF-kappa B/metabolism
• Repressor Proteins/antagonists & inhibitors
• Smoking/adverse effects
• Soot/toxicity
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Transcription Factor AP-1/metabolism

• CA125123 NCI NIH HHS
• AI036211 NIAID NIH HHS
• R01 HL110883 NHLBI NIH HHS
• I01 CX000104 CSRD VA
• R01HL110883 NHLBI NIH HHS
• P30 CA125123 NCI NIH HHS
• I01 BX002221 BLRD VA
• R01 HL117181 NHLBI NIH HHS
• S10 RR024574 NCRR NIH HHS
• RR024574 NCRR NIH HHS
• R01HL117181 NHLBI NIH HHS
• P30 AI036211 NIAID NIH HHS

• Aged
• Female
• Forced Expiratory Volume/genetics
• Genetic Predisposition to Disease
• Genome-Wide Association Study/methods
• Humans
• Lung/physiopathology
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Pulmonary Disease, Chronic Obstructive/genetics
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Smoking/adverse effects
• Smoking/genetics

• R01 MH063706 NIMH NIH HHS
• R01HL59367 NHLBI NIH HHS
• 5R01MH63706:02 NIMH NIH HHS
• R01 HL086694 NHLBI NIH HHS
• U01 HG004402 NHGRI NIH HHS
• U01HG004402 NHGRI NIH HHS
• MR/N01104X/1 Medical Research Council
• R01HL087641 NHLBI NIH HHS
• Wellcome Trust
• 076113/B/04/Z Wellcome Trust
• UL1RR025005 NCRR NIH HHS
• 079895 Wellcome Trust
• UL1 RR025005 NCRR NIH HHS
• R01 HL087679 NHLBI NIH HHS
• R01 HL059367 NHLBI NIH HHS
• 068545/Z/02 Wellcome Trust
• G1001799 Medical Research Council
• 1RL1MH083268-01 NIMH NIH HHS
• G1000861 Medical Research Council
• MC_PC_12010 Medical Research Council
• U01 DK062418 NIDDK NIH HHS
• MC_PC_U127561128 Medical Research Council
• Z01 ES025045-08 Intramural NIH HHS
• G0500539 Medical Research Council
• MOP-123369 CIHR
• G0000934 Medical Research Council
• 5R01HL087679-02 NHLBI NIH HHS
• RL1 MH083268 NIMH NIH HHS
• G0902313 Medical Research Council
• Chief Scientist Office
• R01 HL087641 NHLBI NIH HHS
• R01HL086694 NHLBI NIH HHS
• G0600705 Medical Research Council

The tumor suppressor gene p53 regulates a wide range of cellular processes including cell cycle progression, proliferation, apoptosis and tissue development and remodeling. Lung cell apoptosis and tissue remodeling have critical roles in many lung diseases. Abnormal proliferation or resistance to apoptosis of lung cells will lead to structural changes of many lung tissues, including the pulmonary vascular wall, small airways and lung parenchyma. Among the many lung diseases caused by vascular cell apoptosis and tissue remodeling are chronic obstructive pulmonary disease, bronchial asthma and pulmonary arterial hypertension. Recent advances in biology and medicine have provided new insights and have resulted in new therapeutic strategies for tissue remodeling in human and animal models. This review is focused on lung disease susceptibility associated with the p53 pathway and describes molecular mechanisms upstream and downstream of p53 in lung tissue remodeling. Improved understanding of structural changes associated with pulmonary vascular remodeling and lung cell apoptosis induced by the p53 pathway may new provide therapeutic targets.

• Chronic obstructive pulmonary disease
• Pulmonary hypertension
• Asthma
• p21
• Mouse double minute 2 homolog

• epigenetics
• histone deacetylase
• microRNA

• Biomarker
• DNA methyltransferase inhibitors
• DNA modification
• Polycomb
• chronic obstructive pulmonary disease
• emphysema
• histone deacetylase activators

Epigenetic events are differentially expressed in the lungs and airways of patients with chronic obstructive pulmonary disease (COPD). Moreover, epigenetic mechanisms are involved in the skeletal (peripheral) muscle dysfunction of COPD patients. Whether epigenetic events may also regulate respiratory muscle dysfunction in COPD remains unknown. We hypothesized that epigenetic mechanisms would be differentially expressed in the main inspiratory muscle (diaphragm) of patients with COPD of a wide range of disease severity compared to healthy controls. In diaphragm muscle specimens (thoracotomy due to lung localized neoplasms) of sedentary patients with mild-to-moderate and severe COPD, with preserved body composition, and sedentary healthy controls, expression of muscle-enriched microRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), total DNA methylation and protein acetylation, small ubiquitin-related modifier (SUMO) ligases, muscle-specific transcription factors, and muscle structure were explored. All subjects were also clinically evaluated: lung and muscle functions and exercise capacity. Compared to healthy controls, patients exhibited moderate airflow limitation and diffusion capacity, and reduced exercise tolerance and transdiaphragmatic strength. Moreover, in the diaphragm of the COPD patients, muscle-specific microRNA expression was downregulated, while HDAC4 and myocyte enhancer factor (MEF)2C protein levels were higher, and DNA methylation levels, muscle fiber types and sizes did not differ between patients and controls. In the main respiratory muscle of COPD patients with a wide range of disease severity and normal body composition, muscle-specific microRNAs were downregulated, while HDAC4 and MEF2C levels were upregulated. It is likely that these epigenetic events act as biological adaptive mechanisms to better overcome the continuous inspiratory loads of the respiratory system in COPD. These findings may offer novel therapeutic strategies to specifically target respiratory muscle dysfunction in patients with COPD.

• Cancer
• HDAC inhibitors
• HDAC2
• RLIM
• Sumoylation
• p53

• cigarette smoke
• airway epithelial cells
• reactive oxygen species

• Androstadienes/pharmacology
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Carbocysteine/pharmacology
• Cell Line
• Cell Survival/drug effects
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Fluticasone
• Glutathione/metabolism
• Heme Oxygenase-1/metabolism
• Histone Deacetylase 2/metabolism
• Humans
• NF-E2-Related Factor 2/metabolism
• Necrosis
• Oxidative Stress/drug effects
• Plant Extracts/chemistry
• Plant Extracts/toxicity
• Reactive Oxygen Species/metabolism
• Nicotiana/chemistry

• Animals
• Caspase 3/metabolism
• Ceramides/biosynthesis
• Ceramides/metabolism
• Emphysema/chemically induced
• Emphysema/drug therapy
• Emphysema/metabolism
• Fenretinide/chemistry
• Fenretinide/toxicity
• Gene Expression Regulation/drug effects
• Histone Deacetylase 2/metabolism
• Humans
• Hypoxia-Inducible Factor 1/metabolism
• Lysophospholipids/administration & dosage
• Male
• NF-E2-Related Factor 2/metabolism
• Phosphotransferases (Alcohol Group Acceptor)/metabolism
• Protective Agents/administration & dosage
• Pulmonary Alveoli/drug effects
• Pulmonary Alveoli/metabolism
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Sphingosine/administration & dosage
• Sphingosine/analogs & derivatives
• Vascular Endothelial Growth Factor A/metabolism

• N01HR46160 NHLBI NIH HHS
• N01-HR-46160-3 NHLBI NIH HHS

• er quality control
• genetic diseases
• histone deacetylase
• histone deacetylase inhibitors
• protein misfolding
• α1-antitrypsin
• α1-antitrypsin deficiency
• calnexin
• hdac7
• proteostasis

• Calnexin/genetics
• Calnexin/metabolism
• Cell Line
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum/metabolism
• Gene Expression/drug effects
• HCT116 Cells
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylases/genetics
• Histone Deacetylases/metabolism
• Humans
• Hydroxamic Acids/pharmacology
• Immunoblotting
• Liver/metabolism
• Membrane Glycoproteins/genetics
• Membrane Glycoproteins/metabolism
• Mutation
• Oxidoreductases/genetics
• Oxidoreductases/metabolism
• Protein Folding
• Protein Transport/drug effects
• Proteostasis Deficiencies/blood
• Proteostasis Deficiencies/genetics
• Proteostasis Deficiencies/prevention & control
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Vorinostat
• alpha 1-Antitrypsin/blood
• alpha 1-Antitrypsin/genetics
• alpha 1-Antitrypsin/metabolism
• alpha 1-Antitrypsin Deficiency/blood
• alpha 1-Antitrypsin Deficiency/genetics
• alpha 1-Antitrypsin Deficiency/prevention & control

• R01 GM042336 NIGMS NIH HHS
• R01 GM033301 NIGMS NIH HHS
• GM42336 NIGMS NIH HHS
• HL15674 NHLBI NIH HHS
• R01 HL095524 NHLBI NIH HHS
• R01 HL079442 NHLBI NIH HHS
• GM33301 NIGMS NIH HHS

• Adult
• Aged
• Cells, Cultured
• Endothelium, Vascular/metabolism
• Endothelium, Vascular/pathology
• Female
• Gene Expression Regulation/physiology
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Lung/metabolism
• Lung/pathology
• Male
• MicroRNAs/metabolism
• Middle Aged
• Phosphorylation
• Proto-Oncogene Proteins c-akt/metabolism
• Pulmonary Disease, Chronic Obstructive/etiology
• Pulmonary Disease, Chronic Obstructive/metabolism
• Pulmonary Disease, Chronic Obstructive/pathology
• Severity of Illness Index
• Transfection
• Tumor Suppressor Protein p53/metabolism
• Vascular Endothelial Growth Factor A/metabolism

• N01HR46160 NHLBI NIH HHS
• N01-HR-46160-3 NHLBI NIH HHS

• Adaptation, Physiological/genetics
• Aged
• Cell Hypoxia/genetics
• Cells, Cultured
• Erythropoietin/genetics
• Female
• Gene Expression/genetics
• Histone Deacetylases/deficiency
• Histone Deacetylases/genetics
• Humans
• Hypoxia/genetics
• Hypoxia/physiopathology
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Male
• Middle Aged
• Monocytes/metabolism
• Promoter Regions, Genetic/genetics
• Pulmonary Disease, Chronic Obstructive/genetics
• Pulmonary Disease, Chronic Obstructive/physiopathology
• RNA, Messenger/genetics
• Statistics as Topic
• Transcriptional Activation/genetics
• Vascular Endothelial Growth Factor A/genetics

• Wellcome Trust
• 076472/Z/05/Z Wellcome Trust