Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor

Dai, Zhi; Zhu, Maggie M.; Peng, Yi; Machireddy, Narsa; Evans, Colin E.; Machado, Roberto F.; Zhang, Xianming; Zhao, You Yang

doi:10.1164/rccm.201710-2079oc

Cited by 141 publications

(136 citation statements)

References 51 publications

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“…The critical role of HIF2 in the development of hypoxia-induced PH has raised significant interest in targeting HIF2 for treatment of PH patients. In fact, one study has already demonstrated a quite effective role of a HIF2 inhibitor in reversing PH in animal models (40). However, small animal models for PH have well-recognized limitations (41).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Poth

Zhang³

et al. 2019

Eur Respir J

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“…Strategies that target the inhibition of HIF transcription in PH patients could be an interesting new perspective in the treatment of hypertension. For example, it has been demonstrated that HIF-2 inhibited by C76 is capable of relieving pulmonary artery blood pressure in different models ( Dai et al, 2018 ).…”

Section: Hypoxia-inducible Factors and Potential Therapeutic Targetsmentioning

confidence: 99%

Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1

Liu¹,

Galli

Wang

et al. 2020

Front. Physiol.

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Insufficient oxygen availability (hypoxia) is a precursor to numerous cardiovascular diseases, including atherosclerosis, pulmonary hypertension, and heart failure. The main site of hypoxic injury in the human body is the mitochondria, where oxygen acts as the final electron acceptor in the process of oxidative phosphorylation. Hypoxia-inducible factor (HIF) is activated in hypoxic conditions and acts as an important modulator of diverse target genes in the human body. The downstream genes of HIF include vital modulators of cardiovascular-related signaling pathways. Therefore, it is hypothesized that HIF represents a potential therapeutic target for the treatment and prevention of cardiovascular diseases. In this short review, we introduce the pathophysiology of hypoxic injury in cardiovascular disease, and we conclude from convincing evidence that HIF can modulate relevant cardioprotective signaling pathways.

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“…Although increased HIF2α protein stability has been identified in pulmonary vascular occlusive lesions from both IPAH patients and rodent PH models, the mechanistic role of Recent studies by Dai et al [39] and Hu and colleagues [40] offers further support for the important role of HIF2α in PH and confirmed many of these inflammatory and signalling target genes. Furthermore, Hu et al utilised PT2567 in a hypobaric hypoxic rat model of PH and reported a reduction in both pulmonary arterial pressures and vascular remodelling [40].…”

Section: Discussionmentioning

confidence: 96%

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension

et al. 2020

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Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

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Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor

Abstract: These findings demonstrate that pharmacological inhibition of HIF-2α is a promising novel therapeutic strategy for the treatment of severe vascular remodeling and right heart failure in patients with PAH.

Cited by 141 publications

References 51 publications

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

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

Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension

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