Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Peinsipp, P.
Influence of Sclerostin on Lung Vasculature.
[ Diplomarbeit/Master Thesis (UNI) ] Graz University of Technology; 2022. pp.84.
- Autor*innen der Med Uni Graz:
- Biasin Valentina
- Betreuer*innen:
- Biasin Valentina
- Obermayer-Pietsch Barbara
- Altmetrics:
- Abstract:
- Sclerostin, a secreted glycoprotein, is mainly expressed in osteocytes and a well-known negative regulator of bone formation. Recently there has been an increasing number of studies indicating that sclerostin also plays a major role in pulmonary vasculature. These findings are vitally important for scientific research because further understanding of the role of sclerostin could help the development of possible therapies and medication for illnesses like idiopathic pulmonary arterial hypertension (IPAH). The hypothesis of this thesis is that impaired expression of sclerostin in pulmonary vasculature affects the function of lung vascular cells contributing to the development of IPAH. In order to verify our hypothesis, it was necessary to localize the expression of sclerostin, to determine differences in the expression of sclerostin between IPAH and healthy pulmonary arteries (PA) and to analyze the effect of sclerostin on pulmonary vascular cells, specifically on human pulmonary artery smooth muscle cells (hPASMC) and human pulmonary artery endothelial cells (hPAEC). It could be proved, that sclerostin is localized in PA, specifically in hPAEC as well as in hPASMC. Differential expression analysis emphasizes that sclerostin level is increased in PA of IPAH patients compared to healthy donors. HPASMC isolated from donor and IPAH PA do not show significant increase of sclerostin, suggesting that the upregulation observed in IPAH PA compared to donors is most probably caused by an upregulation of sclerostin in hPAEC. As hPAEC possess the receptor for sclerostin, we investigated the possible effect of sclerostin on hPAEC. We observed protective effects of sclerostin pre-treatment on thrombin mediated barrier dysfunction. This effect was not mediated by an influence of sclerostin on VE-Cadherin but rather by an influence on calcium handling. Indeed, sclerostin affects calcium homeostasis of hPAEC by increasing calcium influx and decreasing calcium store depletion. We could also show that sclerostin could have an effect on metabolism of hPAEC, increasing their mitochondrial respiration. In conclusion, these results suggest that sclerostin could be a protective factor for hPAEC during the development of IPAH. Hence, sclerostin could be of major importance for further understanding of molecular mechanisms underlying IPAH. Additional experiments are needed to further elucidate the exact role of sclerostin and possibly make valid therapeutic implications.