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Novel Drugs for the Treatment of Pulmonary Arterial Hypertension: Where Are We Going?

ABSTRACT: Pulmonary arterial hypertension (PAH) is a progressive disease that despite advances in therapy is associated with a 7-year survival of approximately 50%. Several risk factors are associated with developing PAH, include methamphetamine use, scleroderma, human immunodeficiency virus, portal hypertension, and genetic predisposition. PAH can also be idiopathic. There are traditional pathways underlying the pathophysiology of PAH involving nitric oxide, prostacyclin, thromboxane A2, and endothelin-1, resulting in impaired vasodilation, enhanced vasoconstriction and proliferation in the pulmonary vasculature. Established PAH medications targets these pathways; however, this paper aims to discuss novel drugs for treating PAH by targeting new and alternative pathways.

SUBMITTER: Alamri AK

PROVIDER: S-EPMC10074340 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Novel Drugs for the Treatment of Pulmonary Arterial Hypertension: Where Are We Going?

Alamri Ayedh K AK Ma Christy L CL Ryan John J JJ

Drugs 20230405 7

Pulmonary arterial hypertension (PAH) is a progressive disease that despite advances in therapy is associated with a 7-year survival of approximately 50%. Several risk factors are associated with developing PAH, include methamphetamine use, scleroderma, human immunodeficiency virus, portal hypertension, and genetic predisposition. PAH can also be idiopathic. There are traditional pathways underlying the pathophysiology of PAH involving nitric oxide, prostacyclin, thromboxane A2, and endothelin-1 ...[more]

PMID: 37017914

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Project description:AimsPulmonary arterial hypertension (PAH) is a fatal disease without a cure. Previously, we found that transcription factor RUNX1-dependent haematopoietic transformation of endothelial progenitor cells may contribute to the pathogenesis of PAH. However, the therapeutic potential of RUNX1 inhibition to reverse established PAH remains unknown. In the current study, we aimed to determine whether RUNX1 inhibition was sufficient to reverse Sugen/hypoxia (SuHx)-induced pulmonary hypertension (PH) in rats. We also aimed to demonstrate possible mechanisms involved.Methods and resultsWe administered a small molecule specific RUNX1 inhibitor Ro5-3335 before, during, and after the development of SuHx-PH in rats to investigate its therapeutic potential. We quantified lung macrophage recruitment and activation in vivo and in vitro in the presence or absence of the RUNX1 inhibitor. We generated conditional VE-cadherin-CreERT2; ZsGreen mice for labelling adult endothelium and lineage tracing in the SuHx-PH model. We also generated conditional Cdh5-CreERT2; Runx1(flox/flox) mice to delete Runx1 gene in adult endothelium and LysM-Cre; Runx1(flox/flox) mice to delete Runx1 gene in cells of myeloid lineage, and then subjected these mice to SuHx-PH induction. RUNX1 inhibition in vivo effectively prevented the development, blocked the progression, and reversed established SuHx-induced PH in rats. RUNX1 inhibition significantly dampened lung macrophage recruitment and activation. Furthermore, lineage tracing with the inducible VE-cadherin-CreERT2; ZsGreen mice demonstrated that a RUNX1-dependent endothelial to haematopoietic transformation occurred during the development of SuHx-PH. Finally, tissue-specific deletion of Runx1 gene either in adult endothelium or in cells of myeloid lineage prevented the mice from developing SuHx-PH, suggesting that RUNX1 is required for the development of PH.ConclusionBy blocking RUNX1-dependent endothelial to haematopoietic transformation and pulmonary macrophage recruitment and activation, targeting RUNX1 may be as a novel treatment modality for pulmonary arterial hypertension.

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Novel Drugs for the Treatment of Pulmonary Arterial Hypertension: Where Are We Going?

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Novel Drugs for the Treatment of Pulmonary Arterial Hypertension: Where Are We Going?

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