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SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension

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Název: SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension
Autoři: Veith, Christine, Vartürk-Özcan, Ipek, Wujak, Magdalena, Hadzic, Stefan, Wu, Cheng-Yu, Knoepp, Fenja, Kraut, Simone, Petrovic, Aleksandar, Gredic, Marija, Pak, Oleg, Brosien, Monika, Heimbrodt, Marie, Wilhelm, Jochen, Weisel, Friederike C., Malkmus, Kathrin, Schäfer, Katharina, Gall, Henning, Tello, Khodr, Kosanovic, Djuro, Sydykov, Akylbek, Sarybaev, Akpay, Günther, Andreas, Brandes, Ralf P., Seeger, Werner, Grimminger, Friedrich, Ghofrani, Hossein A., Schermuly, Ralph T., Kwapiszewska, Grazyna, Sommer, Natascha, Weissmann, Norbert
Zdroj: Circulation ; volume 145, issue 12, page 916-933 ; ISSN 0009-7322 1524-4539
Informace o vydavateli: Ovid Technologies (Wolters Kluwer Health)
Rok vydání: 2022
Popis: Background: Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMCs) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVECs). On reexposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, the authors aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature. Methods: After microarray analysis, the authors assessed the role of SPARC (secreted protein acidic and rich in cysteine) in PH using lung tissue from idiopathic pulmonary arterial hypertension (IPAH) patients, as well as from chronically hypoxic mice. In vitro studies were conducted in primary human PASMCs and PMVECs. In vivo function of SPARC was proven in chronic hypoxia-induced PH in mice by using an adeno-associated virus–mediated Sparc knockdown approach. Results: C57BL/6J mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent reexposure to normoxia for different time points. Microarray analysis of the pulmonary vascular compartment after laser microdissection identified Sparc as one of the genes downregulated at all reoxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in IPAH, although SPARC plasma levels were not elevated in PH. TGF-β1 (transforming growth factor β1) or HIF2A (hypoxia-inducible factor 2A) signaling pathways induced SPARC expression in human PASMCs. In loss of function studies, SPARC silencing enhanced apoptosis and reduced proliferation. In gain of function studies, elevated SPARC levels induced PASMCs, but not PMVECs, proliferation. Coculture and conditioned medium experiments revealed that PMVECs-secreted SPARC acts as a paracrine factor ...
Druh dokumentu: article in journal/newspaper
Jazyk: English
DOI: 10.1161/circulationaha.121.057001
DOI: 10.1161/CIRCULATIONAHA.121.057001
Dostupnost: https://doi.org/10.1161/circulationaha.121.057001
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.121.057001
Přístupové číslo: edsbas.E26208DA
Databáze: BASE
Popis
Abstrakt:Background: Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMCs) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVECs). On reexposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, the authors aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature. Methods: After microarray analysis, the authors assessed the role of SPARC (secreted protein acidic and rich in cysteine) in PH using lung tissue from idiopathic pulmonary arterial hypertension (IPAH) patients, as well as from chronically hypoxic mice. In vitro studies were conducted in primary human PASMCs and PMVECs. In vivo function of SPARC was proven in chronic hypoxia-induced PH in mice by using an adeno-associated virus–mediated Sparc knockdown approach. Results: C57BL/6J mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent reexposure to normoxia for different time points. Microarray analysis of the pulmonary vascular compartment after laser microdissection identified Sparc as one of the genes downregulated at all reoxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in IPAH, although SPARC plasma levels were not elevated in PH. TGF-β1 (transforming growth factor β1) or HIF2A (hypoxia-inducible factor 2A) signaling pathways induced SPARC expression in human PASMCs. In loss of function studies, SPARC silencing enhanced apoptosis and reduced proliferation. In gain of function studies, elevated SPARC levels induced PASMCs, but not PMVECs, proliferation. Coculture and conditioned medium experiments revealed that PMVECs-secreted SPARC acts as a paracrine factor ...
DOI:10.1161/circulationaha.121.057001