Life sciences · 2026
TBX5-GATA4 interaction aggravates pulmonary artery smooth muscle proliferation and pathogenesis of pulmonary arterial hypertension through transcriptional co-activating CDK18.
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Zhou Wen-Ying, Wu Xin-Lin, Wang Shu-Yu, Zhang Xiao-Yan, Zhang Hang, Chen Shao-Liang, Wang Feng
Аннотация
AIMS: Hypoxia-induced pulmonary arterial hypertension, a frequent complication of chronic respiratory diseases, is recognized as a severe and lethal clinical syndrome. Currently, there are no established pharmacological treatment, highlighting the need to identify targets and mechanism regarding it.
MATERIALS AND METHODS: RNA-seq followed by comprehensive in vitro and in vivo validation was used to examine changes in TBX5 expression in pulmonary arterial smooth muscle cells under hypoxic conditions. The effects of TBX5 knockdown on cell proliferation, pulmonary arterial pressure, and vascular remodeling were assessed, and downstream RNA-seq together with rescue experiments was performed to explore the underlying regulatory mechanisms.
KEY FINDINGS: A marked increase in TBX5 expression was observed in pulmonary arterial smooth muscle cells in response to hypoxia. Knockdown of TBX5 significantly reduced cell proliferation, decreased pulmonary arterial pressure, and slowed vascular remodeling in experimental mouse models. Moreover, GATA4 was found to enhance TBX5 expression and promote cell proliferation. Mechanically, GATA4 and TBX5 formed a transcriptional co-activator complex that targets CDK18, thereby driving the initiation and progression of hypoxia-induced pulmonary arterial hypertension.
SIGNIFICANCE: This study will clarify the role and mechanism of TBX5 in promoting hypoxia-induced pulmonary arterial hypertension, provide a theoretical basis for improving the mechanism of hypoxia-induced pulmonary arterial hypertension, thus providing new potential targets for PAH.
MATERIALS AND METHODS: RNA-seq followed by comprehensive in vitro and in vivo validation was used to examine changes in TBX5 expression in pulmonary arterial smooth muscle cells under hypoxic conditions. The effects of TBX5 knockdown on cell proliferation, pulmonary arterial pressure, and vascular remodeling were assessed, and downstream RNA-seq together with rescue experiments was performed to explore the underlying regulatory mechanisms.
KEY FINDINGS: A marked increase in TBX5 expression was observed in pulmonary arterial smooth muscle cells in response to hypoxia. Knockdown of TBX5 significantly reduced cell proliferation, decreased pulmonary arterial pressure, and slowed vascular remodeling in experimental mouse models. Moreover, GATA4 was found to enhance TBX5 expression and promote cell proliferation. Mechanically, GATA4 and TBX5 formed a transcriptional co-activator complex that targets CDK18, thereby driving the initiation and progression of hypoxia-induced pulmonary arterial hypertension.
SIGNIFICANCE: This study will clarify the role and mechanism of TBX5 in promoting hypoxia-induced pulmonary arterial hypertension, provide a theoretical basis for improving the mechanism of hypoxia-induced pulmonary arterial hypertension, thus providing new potential targets for PAH.