Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PDE9A deficiency does not prevent chronic-hypoxic pulmonary hypertension in mice.

ABSTRACT: Inhibition of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterases (PDEs) is a cornerstone of pulmonary arterial hypertension (PAH)-specific therapy. PDE9A, expressed in the heart and lung tissue, has the highest affinity for cGMP of all known PDEs. PDE9A deficiency protects mice against chronic left ventricular (LV) pressure overload via increased natriuretic peptide (NP)-dependent cGMP signaling. Chronic-hypoxic pulmonary hypertension (CH-PH) is a model of chronic right ventricular (RV) pressure overload, and previous studies have demonstrated a protective role for NPs in the murine model. Therefore, we hypothesized that PDE9A deficiency would promote NP-dependent cGMP signaling and prevent RV remodeling in the CH-PH model, analogous to findings in the LV. We exposed wild-type and PDE9A-deficient (Pde9a^-/- ) C57BL/6 mice to CH-PH for 3 weeks. We measured RV pressure, hypertrophy, and levels of lung and RV cGMP, PDE9A, PDE5A, and phosphorylation of the protein kinase G substrate VASP (vasodilatory-stimulated phosphoprotein) after CH-PH. In wild-type mice, CH-PH was associated with increased circulating ANP and lung PDE5A, but no increase in cGMP, PDE9A, or VASP phosphorylation. Downstream effectors of cGMP were not increased in Pde9a^-/- mice exposed to CH-PH compared with Pde9a^+/+ littermates, and CH-PH induced increases in RV pressure and hypertrophy were not attenuated in knockout mice. Taken together, these findings argue against a prominent role for PDE9A in the murine CH-PH model.

SUBMITTER: Kolb TM

PROVIDER: S-EPMC8474007 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Hypoxic pulmonary hypertension study

Project description:These microarray studies were performed using whole lungs of BALB/C mice during development of hypoxia-induced pulmonary hypertension (days 1-21) and resolution of pulmonary hypertension after return to normoxia (days 22-35) . Mice were sampled during nine time-points and each time-point was replicated 4 times (with dye swapping). Keywords = hypoxia Keywords = pulmonary hypertension

2010-06-10 | E-GEOD-1909 | biostudies-arrayexpress

Digoxin inhibits development of hypoxic pulmonary hypertension in mice.

Project description:Chronic hypoxia is an inciting factor for the development of pulmonary arterial hypertension. The mechanisms involved in the development of hypoxic pulmonary hypertension (HPH) include hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cell (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Recently, digoxin was shown to inhibit HIF-1 transcriptional activity. In this study, we tested the hypothesis that digoxin could prevent and reverse the development of HPH. Mice were injected daily with saline or digoxin and exposed to room air or ambient hypoxia for 3 wk. Treatment with digoxin attenuated the development of right ventricle (RV) hypertrophy and prevented the pulmonary vascular remodeling and increases in PASMC [Ca(2+)](i), pH, and RV pressure that occur in mice exposed to chronic hypoxia. When started after pulmonary hypertension was established, digoxin attenuated the hypoxia-induced increases in RV pressure and PASMC pH and [Ca(2+)](i). These preclinical data support a role for HIF-1 inhibitors in the treatment of HPH.

| S-EPMC3268303 | biostudies-other

Hypoxic pulmonary hypertension study

2005-03-16 | GSE1909 | GEO

BMPR2 vs hypoxic pulmonary hypertension

Project description:Comparison of lung from hypoxic PAH to SM22-tet-BMPR2delx4+ PAH, with three different types of control Keywords: genetic modification, disease state response, stress response

2005-06-10 | GSE2773 | GEO

Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension.

Project description:Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway leading to prostacyclin (PGI2) production. Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels, but the importance of this deficiency for lung vascular remodeling remains unclear. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. To study this hypothesis, transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3.7-kb human surfactant protein-C (SP-C) promoter and the rat PGIS cDNA. Transgenic mice (Tg+) and nontransgenic littermates (Tg-) were subjected to a simulated altitude of 17,000 ft for 5 weeks, and right ventricular systolic pressure (RVSP) was measured. Histology was performed on the lungs. The Tg+ mice produced 2-fold more pulmonary 6-keto prostaglandin F1alpha (PGF1alpha) levels than did Tg- mice. After exposure to chronic hypobaric hypoxia, Tg+ mice have lower RVSP than do Tg- mice. Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg+ mice in comparison with vessel wall hypertrophy in the Tg- mice. These studies demonstrate that Tg+ mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia. This has important implications for the pathogenesis and treatment of severe pulmonary hypertension.

| S-EPMC408370 | biostudies-literature

Whole transcriptome analysis of hypoxic pulmonary hypertension

Project description:Non-coding RNA plays an important regulatory role in the occurrence and development of hypoxic pulmonary hypertension (HPH). Therefore, we use high-throughput RNA sequence and bioinformatics methods to analyze the whole transcriptome HPH rats in lung tissue.

2021-09-01 | GSE159668 | GEO

Increased intracellular Cl<sup>-</sup> concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension.

Project description:Chloride channels play an important role in regulating smooth muscle contraction and proliferation, and contribute to the enhanced constriction of pulmonary arteries (PAs) in pulmonary hypertension (PH). The intracellular Cl- concentration ([Cl-]i), tightly regulated by various Cl- transporters, determines the driving force for Cl- conductance, thereby the functional outcome of Cl- channel activation. This study characterizes for the first time the expression profile of Cl- transporters/exchangers in PA smooth muscle and provides the first evidence that the intracellular Cl- homeostasis is altered in PA smooth muscle cells (PASMCs) associated with chronic hypoxic PH (CHPH). Quantitative RT-PCR revealed that the endothelium-denuded intralobar PA of rats expressed Slc12a gene family-encoded Na-K-2Cl cotransporter 1 (NKCC1), K-Cl cotransporters (KCC) 1, 3, and 4, and Slc4a gene family-encoded Na+-independent and Na+-dependent Cl-/HCO3- exchangers. Exposure of rats to chronic hypoxia (10% O2, 3 wk) caused CHPH and selectively increased the expression of Cl--accumulating NKCC1 and reduced the Cl--extruding KCC4. The intracellular Cl- concentration ([Cl-]i) averaged at 45 mM and 47 mM in normoxic PASMCs as determined by fluorescent indicator MEQ and by gramicidin-perforated patch-clamp technique, respectively. The ([Cl-]i was increased by ∼10 mM in PASMCs of rats with CHPH. Future studies are warranted to further establish the hypothesis that the altered intracellular Cl- homeostasis contributes to the pathogenesis of CHPH.

| S-EPMC8526344 | biostudies-literature

Activation of Lung Macrophages in Hypoxic Pulmonary Hypertension

Project description:Studies in various animal models suggest an important role for pulmonary macrophages in the pathogenesis of pulmonary hypertension (PH). Yet, the molecular mechanisms characterizing the functional macrophage phenotype relative to time and pulmonary localization/compartmentalization remain largely unknown. Here, we utilized a hypoxic murine model of PH in combination with flow cytometry assisted cell sorting (FACS) to quantify and isolate lung macrophages from two compartments over time and characterized their programing via RNA sequencing (RNAseq) approaches. In response to hypoxia, we found an early increase in macrophage number that was restricted to the interstitial/perivascular compartment, without recruitment of macrophages to the alveolar compartment or changes in the number of resident alveolar macrophages. Principle component analysis demonstrated significant differences in overall gene expression between alveolar (AMs) and interstitial macrophages (IMs) at baseline and after 4 and 14 days hypoxic exposure. AM’s at both day 4 and 14 and IM’s at day 4 shared a conserved “hypoxia program” characterized by mitochondrial dysfunction, pro-inflammatory gene activation and mTORC1 signaling, while IM’s at day 14 demonstrated a unique anti-inflammatory/ pro-reparative programming state. We conclude that the pathogenesis of vascular remodeling in hypoxic PH involves an early compartment independent activation of lung macrophages towards a conserved hypoxia program, with the development of compartment specific programs later on in the course of disease. Thus, harnessing time and compartment specific differences in lung macrophage polarization needs to be considered in the therapeutic targeting of macrophages in hypoxic PH and potentially other inflammatory lung diseases.

2017-04-03 | GSE87602 | GEO

Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.

Project description:Calcification is a major risk factor for vascular integrity. This pathological symptom and the underlying mechanisms in hypoxic pulmonary artery hypertension remain elusive. Here we report that pulmonary vascular medial calcification is elevated in pulmonary artery hypertension models as a result of an osteoblastic phenotype change of pulmonary arterial smooth muscle cells induced by hypoxia. Notably, inhibiting store-operated calcium channels significantly decreased osteoblastic differentiation and calcification of pulmonary arterial smooth muscle cells under hypoxia. We identified granzyme B, a major constituent of cytotoxic T lymphocytes/natural killer cell granules involved in apoptosis, as the main regulator of pulmonary arterial calcification. Overexpression of granzyme B blocked the mineralization through its effect on store-operated calcium channels in cultured pulmonary arterial smooth muscle cells under hypoxic conditions. Mice with overexpression of granzyme B exposed to hypoxia for 3 weeks showed attenuated vascular calcification and pathological progression of hypoxic pulmonary arterial hypertension. Our findings emphasize the central function of granzyme B in coordinating vascular calcification in hypoxic pulmonary arterial hypertension.

| S-EPMC5833422 | biostudies-literature

Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice.

Project description:Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. Conversely, iron supplementation has been shown to be beneficial in both settings. The mechanisms underlying the effects of iron availability are not known, due to lack of understanding of how cells of the pulmonary vasculature respond to changes in iron levels. The iron export protein ferroportin (FPN) and its antagonist peptide hepcidin control systemic iron levels by regulating release from the gut and spleen, the sites of absorption and recycling, respectively. We found FPN to be present in pulmonary arterial smooth muscle cells (PASMCs) and regulated by hepcidin cell autonomously. To interrogate the importance of this regulation, we generated mice with smooth muscle-specific knock in of the hepcidin-resistant isoform fpn C326Y. While retaining normal systemic iron levels, this model developed PAH and right heart failure as a consequence of intracellular iron deficiency and increased expression of the vasoconstrictor endothelin-1 (ET-1) within PASMCs. PAH was prevented and reversed by i.v. iron and by the ET receptor antagonist BQ-123. The regulation of ET-1 by iron was also demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II. Such mutations were further associated with dysregulation of the HAMP/FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function. It offers a mechanistic underpinning for the known effects of iron availability in humans.

| S-EPMC6600981 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data