Death-associated protein kinase 1 prevents hypoxia-induced metabolic shift and pulmonary arterial smooth muscle cell proliferation in PAH.

Autor: Seidel LM; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Thudium J; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Smith C; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Sapehia V; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Sommer N; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Wujak M; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany; Department of Medicinal Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland., Weissmann N; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Seeger W; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Institute for Lung Health, Giessen, Germany., Schermuly RT; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany., Novoyatleva T; Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany. Electronic address: tatyana.novoyatleva@innere.med.uni-giessen.de.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2024 Nov 30; Vol. 127, pp. 111527. Date of Electronic Publication: 2024 Nov 30.
DOI: 10.1016/j.cellsig.2024.111527
Abstrakt: Pulmonary hypertension (PH) is a general term used to describe high blood pressure in the lungs from any cause. Pulmonary arterial hypertension (PAH) is a progressive, and fatal disease that causes the walls of the pulmonary arteries to tighten and stiffen. One of the major characteristics of PAH is the hyperproliferation and resistance to apoptosis of vascular cells, which trigger excessive pulmonary vascular remodeling and vasoconstriction. The death-associated protein DAP-kinase (DAPK) is a tumor suppressor and Ser/Thr protein kinase, which was previously shown to regulate the hypoxia inducible factor (HIF)-1α. Against this background, we now show that DAPK1 regulates human pulmonary arterial smooth muscle cell (hPASMC) proliferation and energy metabolism in a HIF-dependent manner. DAPK1 expression is downregulated in pulmonary vessels and PASMCs of human and experimental PH lungs. Reduced expression of DAPK1 in hypoxia and non-hypoxia PAH-PASMCs correlates with increased expression of HIF-1/2α. RNA interference-mediated depletion of DAPK1 leads to fundamental metabolic changes, including a significantly decreased rate of oxidative phosphorylation associated with enhanced expression of both HIF-1α and HIF-2α and glycolytic enzymes, as hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and an integrator between the glycolysis and citric acid cycle, pyruvate dehydrogenase kinase 1 (PDK1). DAPK1 ablation in healthy donor hPASMCs leads to an increase in proliferation, while its overexpression provides the opposite effects. Together our data indicate that DAPK1 serves as a new inhibitor of the pro-proliferative and glycolytic phenotype of PH in PASMCs acting via HIF-signaling pathway.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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