Lumican deficiency promotes pulmonary arterial remodeling

Ying Ju Lai*, Winston W.Y. Kao, Yung Hsin Yeh, Wei Jan Chen, Pao-Hsien Chu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

5 Scopus citations

Abstract

Pulmonary arterial hypertension (PAH) is caused by progressive extracellular matrix disorganization and increased pulmonary vascular cell proliferation. Lumican is a member of the small leucine-rich proteoglycan family that controls cell proliferation, and is a potential endogenous modulator of TGF-β signaling pathway. We show that the decreased lumican protein levels in pulmonary arterial smooth muscle cells (PASMCs) is related to the vascular remodeling and stiffening observed in PAH. The role of lumican in PASMC accumulation and activation in response to pulmonary vascular remodeling remains unclear and we hypothesized that the loss of lumican in PASMCs promotes the development of PAH. Our aim was to establish that lumican plays a pivotal role in modulating pathological vascular remodeling in humans using a rat model of monocrotaline-induced PAH and chronically hypoxic mice. We found that mice with a homozygous deletion of lumican (Lum-/-) showed severe pulmonary arterial remodeling and right ventricular hypertrophy in response to hypoxia, and these effects in mice with chronic hypoxia-induced pulmonary hypertension were successfully treated by the administration of a lumican C-terminal peptide (LumC13C-A, lumikine). We identified a mechanistic link by which lumican signaling prevents the activation of phosphorylated AKT, resulting in the suppression of PASMC proliferation. Lumican deficiency promotes pulmonary arterial remodeling. Administration of lumikine reverses the PAH pathogenesis caused by hypoxia-induced experimental PAH. Lumican is an antiproliferative target that functions to suppress pAKT activation during pathogenesis.

Original languageEnglish
Pages (from-to)63-81
Number of pages19
JournalTranslational Research
Volume237
DOIs
StatePublished - 11 2021

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© 2021 Elsevier Inc.

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