Abstracts From PVRI 2026 Dublin

https://doi.org/10.1002/pul2.70315 

A001 Targeting ZIP12 to Modulate Intracellular Zinc and Vascular Dysfunction in Pulmonary Arterial Hypertension

Mr Iyobel Kibreab, Dr Chien-Nien Chen, Dr Stephanie Hopley, Dr Richard Butt, Prof Martin Wilkins, Prof Lan Zhao
Imperial College London, London, United Kingdom, Apollo Therapeutics Limited, Cambridge, United Kingdom

Pulmonary arterial hypertension (PAH) is a progressive vascular disorder characterized by excessive pulmonary vasoconstriction and remodeling of peripheral pulmonary arteries. Disruption of intracellular zinc homeostasis has emerged as a potential contributor to disease pathogenesis, yet its mechanistic role remains poorly understood. Previous work from our laboratory identified upregulation of the zinc transporter ZIP12 in the pulmonary vasculature of patients with idiopathic PAH (IPAH). ZIP12 facilitates the influx of zinc into the intracellular space, and its dysregulation is associated with pathological cellular behaviors such as proliferation, migration, and metabolic reprogramming. In this study, we investigated the effects of ZIP12 inhibition using APL-9796, a novel humanised monoclonal antibody on intracellular labile zinc levels, cellular proliferation, and vasoconstrictive responses using pulmonary artery fibroblasts (PAAFs) derived from IPAH patients and pulmonary smooth muscle cells (PASMCs). Western blot analysis confirmed ZIP12 upregulation in IPAH-derived PAAFs and in PASMCs exposed to hypoxia or platelet-derived growth factor (PDGF). High-throughput FRET-based zinc imaging revealed elevated intracellular labile zinc in these cells, which was significantly attenuated by APL-9796 treatment. BrdU incorporation assays demonstrated that APL-9796 reduced hyperproliferation in IPAH PAFs and PDGF/hypoxia-stimulated PASMCs. APL-9796 also reduced the stress fibre formation and myosin light chain phosphorylation, indicating suppression of contractile signalling. In engineered pulmonary artery tissues (EPATs), APL-9796 mitigated PDGF-induced vasoconstriction, supporting its functional relevance in a 3D vascular model.

Collectively, these findings identify ZIP12 as a key regulator of intracellular zinc homeostasis and a driver of proliferative and vasoconstrictive phenotypes in PAH. Targeting ZIP12 with APL-9796 restored zinc balance and reversing vascular dysfunction in PAH.

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