Suppression of HIF2 signalling attenuates the initiation of hypoxia-induced pulmonary hypertension

Most published studies addressing the role of hypoxia inducible factors (HIFs) in hypoxia-induced pulmonary hypertension development employ models that may not recapitulate the clinical setting, including the use of animals with pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Furthermore, critical questions including how and when HIF signalling contributes to hypoxia-induced pulmonary hypertension remain unanswered. Normal adult rodents in which global HIF1 or HIF2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides (ASO) and small molecule inhibitors) were exposed to short-term (4 days) or chronic (4–5 weeks) hypoxia. Haemodynamic studies were performed, the animals euthanised, and lungs and hearts obtained for pathological and transcriptomic analysis. Cell-type-specific HIF signals for pulmonary hypertension initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type-specific HIF deletion). Global Hif1a deletion in mice did not prevent hypoxia-induced pulmonary hypertension at 5 weeks. Mice with global Hif2a deletion did not survive long-term hypoxia. Partial Hif2a deletion or Hif2-ASO (but not Hif1-ASO) reduced vessel muscularisation, increases in pulmonary arterial pressures and right ventricular hypertrophy in mice exposed to 4–5 weeks of hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated earl...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Pulmonary vascular disease Original Articles: Pulmonary vascular disease Source Type: research

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Publication date: 2020Source: European Journal of Radiology Open, Volume 7Author(s): Hiroki Kamada, Hideki Ota, Yosuke Terui, Koichiro Sugimura, Shigefumi Fukui, Hiroaki Shimokawa, Kei TakaseAbstractPulmonary tumor thrombotic microangiopathy (PTTM) is a specific type of tumor embolism in the small and medium pulmonary arteries, leading to rapid progressive pulmonary hypertension. Antemortem diagnosis of PTTM is extremely difficult. We encountered three patients who were histopathologically or clinically diagnosed with PTTM. In all cases, lung perfused blood volume (PBV) images on dual-energy computed tomography (CT) demons...
Source: European Journal of Radiology Open - Category: Radiology Source Type: research
We describe a fetus at 24 3/7 weeks' gestation that showed ultrasound evidence of anemia, hydrops, and severe growth restriction. Both parents were known to be cis heterozygous carriers for SEA α-thalassemia deletion (αα/–). Cordocentesis confirmed fetal anemia and homozygous α-thalassemia (−/−) in the fetus. Fetal intrauterine transfusions corrected the anemia, treated the hydrops, and improved fetal growth. The postnatal course was complicated by hypoxic respiratory failure and persistent pulmonary hypertension of the newborn, which resolved only after partial volume exchange tra...
Source: American Journal of Perinatology Reports - Category: Perinatology & Neonatology Authors: Tags: Case Report Source Type: research
CONCLUSION: Riociguat improves functional NYHA class, distance in the 6MWD test and quality of life in a real-world patient population. PMID: 31974533 [PubMed - as supplied by publisher]
Source: Biomedical Papers of the Medical Faculty of the Univ Palacky Olomouc Czech Repub - Category: Biomedical Science Tags: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub Source Type: research
CONCLUSIONS: In our cohort, the prevalence of serodiscordant SSc patients was low. They differed from their counterparts in some clinical manifestations. The management of patients with SSc should be guided by both serology and cutaneous subtype. PMID: 31969223 [PubMed - as supplied by publisher]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
ConclusionsContinuously delivering electrically generated NO through a Scoop catheter produces vasodilation of the pulmonary vasculature of awake lambs with pulmonary hypertension. Transtracheal NO delivery may provide a long-term treatment for patients with chronic pulmonary hypertension as an outpatient without requiring a mask or tracheal intubation.
Source: Nitric Oxide - Category: Chemistry Source Type: research
ConclusionFHL-1 pathway is not involved in the control of adverse remodeling in the pressure overloaded RV.
Source: Basic Research in Cardiology - Category: Cardiology Source Type: research
Discussion and conclusion: Our results demonstrated that sildenafil decreased pathological changes in alveoli, bronchioles, interstitial tissue, and arterioles of rats with COPD and PH. PMID: 31967915 [PubMed - in process]
Source: Pharmaceutical Biology - Category: Drugs & Pharmacology Tags: Pharm Biol Source Type: research
Iacobas Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), lung histology, and transcriptomes of six-week-old male rats with PH induced by (1) hypoxia (HO), (2) administration of monocrotaline (CM), or (3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH ...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Article Source Type: research
This study is designed to examine the effects of combined prevention with resveratrol and SR1001 on HPH in rats. The effects of combined prevention with resveratrol and SR1001 and each mono-prevention on the development of HPH, Th17 cells differentiation, expression of guanine nucleotide exchange factor-H1 (GEF-H1), Ras homolog gene family member A (RhoA) and Phosphorylated myosin phosphatase target subunit (MYPT1) were examined. HPH and RV hypertrophy occurred in rats exposed to hypoxia. Compared with normoxia group, the hypoxia group showed significantly increased ratio of Th17 cells. After treatment with resveratrol, HP...
Source: Clinical and Experimental Hypertension - Category: Cardiology Authors: Tags: Clin Exp Hypertens Source Type: research
Authors: Akagi S, Miki T, Sando Y, Fujii N, Sarashina T, Nakamura K, Ito H Abstract Chronic-active Epstein-Barr virus infection (CAEBV) is a rare disease that can lead to pulmonary arterial hypertension (PAH). However, the treatment for CAEBV-associated PAH has not been established. We discuss a case of improved pulmonary hypertension after chemotherapy in a patient with CAEBV-associated PAH. A 44-year old man was admitted to our hospital because of an abnormal electrocardiogram and liver dysfunction detected by annual medical examination. Echocardiography showed a dilated right ventricle and an estimated right ven...
Source: International Heart Journal - Category: Cardiology Tags: Int Heart J Source Type: research
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