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PULMONARY HYPERTENSION

Selective JAG1–NOTCH3 targeting shows potential for treating PAH

Nature Reviews Cardiology volume 19, page 433 (2022)Cite this article

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Pulmonary arterial hypertension (PAH) is a chronic and severe cardiopulmonary disorder characterized by increased pulmonary vascular resistance, often resulting in the development of right ventricular failure. Proliferation of vascular smooth muscle cells (VSMCs) of small pulmonary arteries is a major contributor to pulmonary artery remodelling in PAH. New research shows that different Notch ligands have opposing roles in regulating the proliferation and differentiation of VSMCs in the pulmonary vasculature in PAH. Notably, blocking Jagged 1 (JAG1)-mediated NOTCH3 signalling with a selective monoclonal antibody reversed pulmonary hypertensive vasculopathy without toxic effects in mouse and rat models, suggesting that selectively targeting JAG1–NOTCH3 signalling might be an effective and safe strategy for the treatment of PAH.

The investigators found that VSMCs from small pulmonary arteries of patients with PAH produced high levels of the NOTCH3 ligand JAG1, but had minimal production of the NOTCH3 ligand Delta-like protein 4 (DLL4) compared with VSMCs from individuals without PAH. In vitro experiments showed that JAG1 and DLL4 have opposing functions in human VSMCs from small pulmonary arteries. JAG1 controlled NOTCH3 cleavage and activation and promoted VSMC proliferation in an autocrine manner, whereas DLL4 inhibited NOTCH3 cleavage and signalling and retarded VSMC proliferation. High levels of JAG1 were also observed in VSMCs from mice with hypoxia-induced pulmonary hypertension.

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References

Original article

  • Zhang, Y. et al. JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension. Sci. Transl. Med. 14, eabl5471 (2022)

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Related article

  • Southgate, L. et al. Molecular genetic framework underlying pulmonary arterial hypertension. Nat. Rev. Cardiol. 17, 85–95 (2019)

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  1. Nature Reviews Cardiology http://www.nature.com/nrcardio/

    Irene Fernández-Ruiz

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  1. Irene Fernández-Ruiz
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Correspondence to Irene Fernández-Ruiz.

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Fernández-Ruiz, I. Selective JAG1–NOTCH3 targeting shows potential for treating PAH. Nat Rev Cardiol 19, 433 (2022). https://doi.org/10.1038/s41569-022-00726-5

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  • DOI: https://doi.org/10.1038/s41569-022-00726-5

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