Batool, Mehreen (2023). Role of Six transmembrane Protein of prostate 2 (Stamp2) in Experimental Pulmonary Hypertension. PhD thesis, Universität zu Köln.
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Abstract
Background: Pulmonary hypertension (PH) is a grave disease affecting people around the globe from all walks of life and young to older age groups. The disease is characterised by high pulmonary artery pressure and pulmonary vascular resistance, along with vascular remodeling. Ultimately, PH leads to right ventricular failure and death. The cells in the pulmonary vasculature play a pivotal role in developing the underlying vascular remodeling, where increased proliferation and migration is orchestrated in the presence of inflammation which promotes pathogenic cellular responses. Aim: The aim of this study was to define the role of Stamp2 in the development of PH and to study how the presence or absence of Stamp2 affects disease progression. The prior knowledge that Stamp2 absence leads to elevated inflammation and has a role in inflammatory and cardiovascular diseases paved way for developing our hypothesis which is; Stamp2 protects against PH Results: Lung tissue from hypoxia exposed mice, Sugen-hypoxia exposed rats and PAH patients showed significant downregulation of Stamp2 as compared to control animals and healthy patients, showing that disease is associated with low levels of Stamp2. A causal relationship was further solidified with Stamp2-KO mice showing significantly higher muscularization in the small pulmonary arteries and significantly higher right ventricular systolic pressure (RVSP) as measured by invasive hemodynamic assessment characterizing PH, as compared to WT control. Based on these in-vivo findings we characterized Stamp2 regulation in-vitro in human and mouse pulmonary arterial smooth muscle cells (PASMCs) and human microvascular endothelial cells (HMVECs) under hypoxia and normoxia conditions. Similar to the in-vivo findings, downregulation of Stamp2 under hypoxia was observed for both cell types. The relationship between lack of Stamp2 and PH was further solidified with enhancement of pulmonary inflammation in hypoxia-exposed mouse lungs as compared to control. High mRNA expression of inflammatory cytokines in hypoxia exposed Stamp2-KO mouse lungs and serum along with high CD68+ staining in the lung tissue was found. PASMCs showed significantly higher proliferation and migration rates when treated with macrophage supernatant from Stamp2-KO mice as compared to the WT control, which likely contributes to developing pulmonary vascular remodelling. MCP-1, CXCL12 and IL-6 were found to be few of the active cytokines causing these cross-talks between macrophages and PASMCs, as their inhibition effectively prevented these actions mediated by macrophage supernatant. Conclusions: These results show that Stamp2 acts as a protective factor against PH development in both human and mouse. PH progression is associated with Stamp2 downregulation, and lack of Stamp2 promotes pathogenic cellular responses and results in enhanced development of PH. Hence, low expression of Stamp2 may mark the presence of disease, and strategies to upregulate or maintain Stamp2 expression may represent a novel therapeutic intervention.
Item Type: | Thesis (PhD thesis) | ||||||||
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URN: | urn:nbn:de:hbz:38-722850 | ||||||||
Date: | 2023 | ||||||||
Publisher: | Printhaus, Offenbach | ||||||||
Language: | English | ||||||||
Faculty: | Faculty of Medicine | ||||||||
Divisions: | COPT.ZENTRUM | ||||||||
Subjects: | Natural sciences and mathematics Medical sciences Medicine |
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Date of oral exam: | 4 October 2023 | ||||||||
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Refereed: | Yes | ||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/72285 |
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