The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice
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ORIGINAL CONTRIBUTION
The six‑transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice Mehreen Batool1 · Eva M. Berghausen1 · Mario Zierden1 · Marius Vantler1 · Ralph T. Schermuly2,3 · Stephan Baldus1 · Stephan Rosenkranz1 · Henrik ten Freyhaus1 Received: 20 August 2020 / Accepted: 15 October 2020 © The Author(s) 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 S tamp2−/− or WT macrophages. S tamp2−/− 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. Keywords Pulmonary hypertension · Inflammation · Stamp2 · Vascular remodeling · Macrophages
Introduction
Mehreen Batool and Eva M. Berghausen have contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-00826-8) contains supplementary material, which is available to authorized users. * Henrik ten Freyhaus henrik.ten‑freyhaus@uk‑koeln.de 1
Cologne Cardiovascular Research Center (CCRC), and Center for Molecular Medicine Cologne (CMMC), Klinik III Für Innere Medizin, Herzzentrum Der Universität Zu Köln, Kerpener Str. 62, 50937 Köln, Germany
2
Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany
3
German Center for Lung Research (DZL), Giessen, Germany
Pulmonary arterial hypertension (PAH) is characterized by chronic elevation of pulmonary arterial pressure and pulmonary vascular resistance, affect
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