Zinc-Induced PKCδ-dependent Phosphorylation of MTF-1 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension

Sep 30, 2026

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Pulmonary hypertension is propelled by pulmonary vascular remodeling, where the zinc-sensing transcription factor metal-responsive transcription factor 1 (MTF-1) is implicated as a key regulator. Using hypoxia-induced pulmonary hypertension models and cultured pulmonary arterial smooth muscle cells, the study dissects the PKCδ/MTF-1/placental growth factor (PlGF) axis. Under hypoxia, elevated intracellular zinc activates PKCδ and drives MTF-1 phosphorylation at Ser304, enabling nuclear translocation and PlGF transcription. Ser304 mutation or MTF-1 knockdown suppresses PASMC proliferation and migration, while Gö 6983 blocks downstream signaling. In vivo, increased MTF-1 and PlGF occur in Su/Hx-PH rat pulmonary vessels, and APTO-253 attenuates remodeling and improves hemodynamics, identifying zinc/PKCδ/MTF-1/PlGF as a therapeutic target.

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CategoryHealthcare

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1. Introduction

Ivyspring International Publisher InternationalJournal of Biological Sciences 2026; 22(2): 823-840. doi: 10.7150/ijbs.124664 Research Paper Zinc-Induced PKCδ-dependent Phosphorylation of MTF-1 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Ai Chen, PhD1,2*; Yan Yan, PhD3*; Rong Cao, MD1*; Kexin Cai, MD1; Guili Lian, PhD1; Wenqin Cai, MD1,2􀀍; Jianfu Zhou, PhD4􀀍; Liangdi Xie, PhD, FESC, FACC1,2􀀍 1. Department of Geriatrics, Fujian Hypertension Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China. 2. International Medical Department, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China. 3. Department of Cardiology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China. 4. Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China. *Ai Chen, Yan Yan and Rong Cao contributed equally to this manuscript. \#Liangdi Xie, Jianfu Zhou and Wenqin Cai contributed equally to this manuscript. 􀀍 Corresponding authors: Liangdi Xie, Department of Geriatrics, Fujian Hypertension Research Institute, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian 350005, China. Email: [ldxield@163.com](ldxield@163.com); Jianfu Zhou, Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian 350005, [China. Email: jzhou@fjmu.edu.cn](China. Email: jzhou@fjmu.edu.cn); Wenqi Cai, Department of Geriatrics, Fujian Hypertension Research Institute, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian 350005, China. Email: [chin8008@fjmu.edu.cn](chin8008@fjmu.edu.cn). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.09.04; Accepted: 2025.11.29; Published: 2026.01.01 Abstract Pulmonary hypertension (PH) is driven by pulmonary vascular remodeling, in which the zinc-sensing transcription factor metal-responsive transcription factor 1 (MTF-1) may play a pivotal regulatory role. Rodent models of hypoxia-induced PH and cultured pulmonary arterial smooth muscle cells (PASMCs) were used to investigate zinc-mediated MTF-1 activation. Phos-tag SDS-PAGE, site-directed mutagenesis, Cleavage Under Targets and Tagmentation (CUT&Tag), and pharmacological inhibitors were employed to dissect the PKCδ/MTF-1/placental growth factor (PlGF) pathway. CUT&Tag profiling revealed prominent MTF-1 enrichment at promoter regions under hypoxia, with significant occupancy at the Plgf locus and enrichment of angiogenesis-related genes. Hypoxia increased intracellular zinc levels, activated PKCδ, and triggered phosphorylation of MTF-1 at Ser304. This modification was essential for MTF-1 nuclear translocation and PlGF transcription. Mutation of Ser304 or MTF-1 knockdown suppressed PASMCs proliferation and migration under hypoxia and zinc exposure. Gö 6983 abrogated MTF-1 phosphorylation and downstream responses, and selective knockdown of PKCδ reproduced these effects, confirming PKCδ as the predominant isoform mediating MTF-1 activation. In vivo, MTF-1 and PlGF were upregulated in pulmonary vessels of Su/Hx-PH rats, while APTO-253 treatment attenuated pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in hypoxic mice. This study identified PKCδ-dependent phosphorylation of MTF-1 at Ser304 as a critical mechanism linking zinc accumulation to PlGF-driven PASMCs proliferation. Targeting the zinc/PKCδ/MTF-1/PlGF axis represented a novel therapeutic strategy for hypoxic PH

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How do the in vivo findings relate to therapeutic intervention?

In Su/Hx-PH rats, MTF-1 and PlGF were upregulated in pulmonary vessels. In hypoxic mice, APTO-253 treatment attenuated pulmonary vascular remodeling and improved cardiopulmonary hemodynamics, indicating therapeutic potential for targeting the zinc/PKCδ/MTF-1/PlGF axis.

Sep 30, 2026

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