Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Nagy, B.
The role of ABCG2 transporter in Pulmonary Hypertension (PH)
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 81
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Olschewski Andrea
- Olschewski Horst
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- Abstract:
- The adenosine triphosphate-binding cassette (ABC)G2 transporter protects cancer cells from chemotherapy but it also protects from pressure overload-induced ventricular dysfunction. It is upregulated in the myocardium of heart failure patients and is clearing hypoxia-induced intracellular metabolites. This study employs ABCG2 knockout (KO) mice to elucidate the relevance of ABCG2 for pulmonary- and cardiac function and structure in chronic hypoxia, and uses human explanted tissues and primary cells to investigate the role of ABCG2 in humans. Our results showed that ABCG2 was present in the main cellular components of the human lung vasculature, and it was upregulated in patients with idiopathic pulmonary hypertension (IPAH). The expression of ABCG2 in pulmonary arterial smooth muscle cells (PASMC) was regulated by platelet derived growth factor (PDGF), and inhibition of the transporter abolished the proliferation of these cells. However, when ABCG2 KO and control mice were subjected to 4 weeks normoxia or hypoxia, there was no difference in hypoxia-induced pulmonary hypertension or vascular remodelling between ABCG2 KO and wild type mice. On the other hand, in hypoxia, KO mice showed pronounced right- (RV) and left (LV) ventricular diastolic dysfunction, manifested by an increase in end-diastolic pressure and myocardial fibrosis, whereas systolic function was preserved. Despite increased ventricular remodelling, capillary density was unaffected by ABCG2 and by hypoxia. In line with these observations ABCG2-deficient mouse and human cardiac fibroblasts showed increased collagen production in hypoxia. As a conclusion, we provide evidence that particularly under hypoxia, loss of ABCG2 leads to biventricular fibrosis with diastolic dysfunction, although it does not affect pulmonary hypertension, RV afterload and capillary density. Our study raises concerns regarding the use of ABCG2 inhibitors in cancer patients especially with hypoxemia or ischemic heart disease, as it might cause drug-induced cardiotoxicity.