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  Adenylate Kinase 4-A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1 alpha Signaling Pathways

Wujak, M., Veith, C., Wu, C.-Y., Wilke, T., Kanbagli, Z. I., Novoyatleva, T., et al. (2021). Adenylate Kinase 4-A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1 alpha Signaling Pathways. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 22(19): 10371. doi:10.3390/ijms221910371.

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 Creators:
Wujak, Magdalena, Author
Veith, Christine, Author
Wu, Cheng-Yu, Author
Wilke, Tessa, Author
Kanbagli, Zeki Ilker, Author
Novoyatleva, Tatyana, Author
Guenther, Andreas, Author
Seeger, Werner1, Author              
Grimminger, Friedrich, Author
Sommer, Natascha, Author
Schermuly, Ralph Theo, Author
Weissmann, Norbert, Author
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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 Abstract: Increased proliferation of pulmonary arterial smooth muscle cells (PASMCs) in response to chronic hypoxia contributes to pulmonary vascular remodeling in pulmonary hypertension (PH). PH shares numerous similarities with cancer, including a metabolic shift towards glycolysis. In lung cancer, adenylate kinase 4 (AK4) promotes metabolic reprogramming and metastasis. Against this background, we show that AK4 regulates cell proliferation and energy metabolism of primary human PASMCs. We demonstrate that chronic hypoxia upregulates AK4 in PASMCs in a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent manner. RNA interference of AK4 decreases the viability and proliferation of PASMCs under both normoxia and chronic hypoxia. AK4 silencing in PASMCs augments mitochondrial respiration and reduces glycolytic metabolism. The observed effects are associated with reduced levels of phosphorylated protein kinase B (Akt) as well as HIF-1 alpha, indicating the existence of an AK4-HIF-1 alpha feedforward loop in hypoxic PASMCs. Finally, we show that AK4 levels are elevated in pulmonary vessels from patients with idiopathic pulmonary arterial hypertension (IPAH), and AK4 silencing decreases glycolytic metabolism of IPAH-PASMCs. We conclude that AK4 is a new metabolic regulator in PASMCs interacting with HIF-1 alpha and Akt signaling pathways to drive the pro-proliferative and glycolytic phenotype of PH.

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 Dates: 2021-09-26
 Publication Status: Published online
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 Rev. Type: -
 Identifiers: ISI: 000756258900001
DOI: 10.3390/ijms221910371
PMID: 34638712
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Title: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Source Genre: Journal
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Pages: - Volume / Issue: 22 (19) Sequence Number: 10371 Start / End Page: - Identifier: -