Selective inhibition of chemokine CCL2/MCP-1 reduces experimental pulmonary hypertension

Kosanovic, Djuro; Dahal, BK; Vroom, Christina; Bieniek, Ewa; Ghofrani, HA; Weissmann, N.; Seeger, Wolfgang; Grimminger, F.; Klussmann, Sven; Eulberg, Dirk; Schermuly, RT

doi:10.1055/s-0033-1345048

Cited by 1 publication

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“…However, to study the role of HIF in PH development, most published studies used models in which HIF deletion or HIF activation (in PHD2 knockout) was initiated in embryonic life (1,(3)(4)(5)(6)(7)(8)10). We think results from such approaches needed to be re-evaluated because 1) all these models are known to exhibit vascular defects in developing embryos and likely in adult mice derived from these embryos (12)(13)(14)(15)(16)(17) and 2) there are examples demonstrating differences in phenotype (baseline as well as stressed) when gene deletion is initiated in the embryo versus in the adult (27)(28)(29). For example, inhibition of monocyte chemoattractant protein 1 (MCP1) initiated in adult animals reduces hypoxia-or MCT-induced PH (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…We think results from such approaches needed to be re-evaluated because 1) all these models are known to exhibit vascular defects in developing embryos and likely in adult mice derived from these embryos (12)(13)(14)(15)(16)(17) and 2) there are examples demonstrating differences in phenotype (baseline as well as stressed) when gene deletion is initiated in the embryo versus in the adult (27)(28)(29). For example, inhibition of monocyte chemoattractant protein 1 (MCP1) initiated in adult animals reduces hypoxia-or MCT-induced PH (27,28). In contrast, MCP-1 or MCP-1 receptor knock-out mice (initiated in the embryo) exhibit spontaneous PH (29).…”

Section: Discussionmentioning

confidence: 99%

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

Poth

Zhang³

et al. 2019

Eur Respir J

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Most published studies addressing the role of HIFs in hypoxia-induced PH development employ models that may not recapitulate the clinical setting, including the use of animals having pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Further, critical questions including how and when HIF-signalling contributes to hypoxia-induced PH remains unanswered.Normal adult rodents in which global HIF1 or 2 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. Hemodynamic studies were performed, the animals euthanized and lungs and heart obtained for pathologic and transcriptomic analysis. Cell-type specific HIF signals for PH initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type specific HIF deletion).Global HIF1α deletion in mice did not prevent hypoxia-induced PH at 5 weeks. Mice with global HIF2α deletion did not survive long-term hypoxia. Partial HIF2α gene deletion, or HIF2-ASO (but not HIF1-ASO) reduced vessel muscularization, rises in pulmonary artery pressures and right ventricular hypertrophy in mice exposed to 4–5 week hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4-day hypoxia as well as vessel musculization, tenascin C accumulation and PH development in rats exposed to 5 week hypoxia. In vitro, HIF2 induced a distinct set of genes in normal pulmonary vascular EC, mediating inflammation and proliferation of EC and SMC. EC HIF2α knockout prevented hypoxia-induced PH in mice.Inhibition of HIF2, not HIF1 can provide a therapeutic approach to prevent the development of hypoxia-induced PH. Future studies are needed to investigate the role of HIFs in PH progression and reversal.

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