Search

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 early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4 days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5 weeks of hypoxia. In vitro, HIF2 induced a distinct set of genes in normal human pulmonary vascular endothelial cells, mediating inflammation and proliferation of endothelial cells and smooth muscle cells. Endothelial Hif2a knockout prevented hypoxia-induced pulmonary hypertension in mice.Inhibition of HIF2 (but not HIF1) can provide a therapeutic approach to prevent the development of hypoxia-induced pulmonary hypertension. Future studies are needed to investigate the role of HIFs in pulmonary hypertension progression and reversal.

Callicarpa nudiflora can be used as a new green plant feed additive in animal production. The main chemical components of Callicarpa nudiflora are flavonoids, phenylpropanoids, terpenoids, volatile oils, etc. These components play different pharmacological roles in anti-inflammatory, hemostatic, antibacterial, and immune enhancement, which can be used in animal production. In order to promote the further development and citation of Callicarpa nudiflora, the paper summarized the pharmacological activity and mechanism of Callicarpa nudiflora, and summarized its research progress in monogastric animal production, providing a reference for the subsequent development of Callicarpa nudiflora. [ABSTRACT FROM AUTHOR]

Chronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation and extracellular matrix (ECM) remodelling. Current therapies for PH, focusing on vasodilatation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development. Although these approaches have produced a large number of compelling PH treatment targets, many promising human drugs have failed in PH clinical trials. Herein, we propose that one contributing factor to these failures is that processes important in PH development may not be good treatment targets in the established phase of chronic PH. We hypothesize that this is due to alterations of chromatin structure in PH cells, resulting in functional differences between the same factor or pathway in normal or early PH cells versus cells in chronic PH. We propose that the high expression of genes involved in the persistently activated phenotype of PH vascular cells is perpetuated by an open chromatin structure and multiple transcription factors (TFs) via the recruitment of high levels of epigenetic regulators including the histone acetylases P300/CBP, histone acetylation readers including BRDs, the Mediator complex and the positive transcription elongation factor (Abstract figure). Thus, determining how gene expression is controlled by examining chromatin structure, TFs and epigenetic regulators associated with aberrantly expressed genes in pulmonary vascular cells in chronic PH, may uncover new PH therapeutic targets. Hypothetical representation of chromatin structure, transcription factors (TFs) and TF co‐regulators in normal (top panel), and persistently "activated" PH vascular cells (lower panel) of genes involved in proliferation, apoptosis‐resistance and pro‐inflammation. We posit that the persistently high expression of these genes in PH vascular cells is due to their "open" chromatin structure, allowing binding of multiple stress‐related TFs and pioneer TF(s), which help maintain an active chromatin structure and high levels of gene expression by recruiting and maintaining high levels of TF co‐factors including epigenetic regulators such as HATs, BRDs and the Mediator Complex (lower panel). Abbreviations: Ac, acetylation; EGR1, early growth response 1; p‐TEFb, positive transcription elongation factor B; Pol II, RNA polymerase II. [ABSTRACT FROM AUTHOR]