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Open Access 01-12-2020 | Pulmonary Hypertension | Original Contribution

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

Authors: Mehreen Batool, Eva M. Berghausen, Mario Zierden, Marius Vantler, Ralph T. Schermuly, Stephan Baldus, Stephan Rosenkranz, Henrik ten Freyhaus

Published in: Basic Research in Cardiology | Issue 6/2020

Abstract

Six-transmembrane protein of prostate (Stamp2) protects from diabetes and atherosclerosis in mice via anti-inflammatory mechanisms. As chronic inflammation is a hallmark of pulmonary arterial hypertension (PAH), we investigated the role of Stamp2. Stamp2 expression was substantially reduced in the lung of humans with idiopathic PAH, as well as in experimental PAH. In Stamp2-deficient mice, hypoxia modestly aggravated pulmonary vascular remodeling and right ventricular pressure compared to WT. As endothelial cell (EC) and pulmonary arterial smooth muscle cell (PASMC) phenotypes drive remodeling in PAH, we explored the role of Stamp2. Knock-down of Stamp2 in human EC neither affected apoptosis, viability, nor release of IL-6. Moreover, Stamp2 deficiency in primary PASMC did not alter mitogenic or migratory properties. As Stamp2 deficiency augmented expression of inflammatory cytokines and numbers of CD68-positive cells in the lung, actions of Stamp2 in macrophages may drive vascular remodeling. Thus, PASMC responses were assessed following treatment with conditioned media of primary Stamp2^−/− or WT macrophages. Stamp2^−/− supernatants induced PASMC proliferation and migration stronger compared to WT. A cytokine array revealed CXCL12, MCP-1 and IL-6 as most relevant candidates. Experiments with neutralizing antibodies confirmed the role of these cytokines in driving Stamp2’s responses. In conclusion, Stamp2 deficiency aggravates pulmonary vascular remodeling via cross-talk between macrophages and PASMC. Despite a substantial pro-inflammatory response, the hemodynamic effect of Stamp2 deficiency is modest suggesting that additional mechanisms apart from inflammation are necessary to induce severe PAH.

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Title: The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice
Authors: Mehreen Batool
Eva M. Berghausen
Mario Zierden
Marius Vantler
Ralph T. Schermuly
Stephan Baldus
Stephan Rosenkranz
Henrik ten Freyhaus
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Pulmonary Hypertension
Pulmonary Hypertension
Cytokines
Pulmonary Hypertension
Pulmonary Hypertension
Published in: Basic Research in Cardiology / Issue 6/2020
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-020-00826-8

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The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

Abstract

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Abstract

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