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.
Highlights
Pulmonary arterial hypertension (PAH) is characterized by chronic elevation of pulmonary arterial pressure and pulmonary vascular resistance, affecting approximately 100 million people worldwide [2, 25]
We analyzed the expression of Stamp2 in two distinct experimental models of PAH and in human idiopathic pulmonary arterial hypertension (IPAH)
In the SuHx rat model of severe PAH, a profound downregulation of Stamp2 protein was found as compared to healthy controls (p < 0.0001) (Fig. 1c), which was corroborated by downregulation of Stamp2 transcript levels by
Summary
Pulmonary arterial hypertension (PAH) is characterized by chronic elevation of pulmonary arterial pressure and pulmonary vascular resistance, affecting approximately 100 million people worldwide [2, 25]. Historical data from PAH patients obtained in the 1980s demonstrate a median survival of only 2.8 years [10], predominantly due to right ventricular failure [14, 46]. The development and approval of targeted therapies led to improvement of survival, morbidity events and quality of life. Because disease-modifying drugs directly targeting the vascular remodeling process in PAH are still lacking, there is an urgent need for novel concepts and therapeutic targets. Dysregulation and apoptosis of endothelial cells and smooth muscle cell responses drive vascular remodeling processes in PAH [12].
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