title: Lack of ABCG2 Leads to Biventricular Dysfunction and Remodeling in Response to Hypoxia.
abstract: Aims:The ATP-binding cassette (ABC)G2 transporter protects the heart from pressure overload-induced ventricular dysfunction but also protects cancer cells from chemotherapeutic agents. It is upregulated in the myocardium of heart failure patients and clears hypoxia-induced intracellular metabolites. This study employs ABCG2 knockout (KO) mice to elucidate the relevance of ABCG2 for cardiac and pulmonary vascular structure and function in chronic hypoxia, and uses human primary cardiac fibroblasts to investigate the potential role of ABCG2 in cardiac fibrosis.Methods and results:ABCG2 KO and control mice (n= 10) were subjected to 4 weeks normoxia or hypoxia. This allowed for investigation of the interaction between genotype and hypoxia (GxH). In hypoxia, KO mice showed pronounced right (RV) and left (LV) ventricular diastolic dysfunction. Compared to normoxia, end-diastolic pressure (EDP) was increased in control vs. KO mice by +1.1 ± 0.3 mmHg vs. +4.8 ± 0.3 mmHg,pfor GxH < 0.001 (RV) and +3.9 ± 0.5 mmHg vs. +11.5 ± 1.6 mmHg, p for GxH = 0.110 (LV). The same applied for myocardial fibrosis with +0.3 ± 0.1% vs. 1.3 ± 0.2%, p for GxH = 0.036 (RV) and +0.06 ± 0.03% vs. +0.36 ± 0.08%,pfor GxH = 0.002 (LV), whereas systolic function and capillary density was unaffected. ABCG2 deficiency did not influence hypoxia-induced pulmonary hypertension or vascular remodeling. In line with these observations, human cardiac fibroblasts showed increased collagen production upon ABCG2 silencing in hypoxia (p for GxH = 0.04).Conclusion:Here we provide evidence for the first time that ABCG2 membrane transporter can play a crucial role in ventricular dysfunction and fibrosis in hypoxia-induced pulmonary hypertension.
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Medical University of GrazGraz, Austria; Ludwig Boltzmann Institute for Lung Vascular ResearchGraz, Austria.
authors.forename: Bence M
authors.initials: BM
authors.lastname: Nagy
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular ResearchGraz, Austria; Institute of Physiology, Medical University of GrazGraz, Austria.
authors.forename: Chandran
authors.initials: C
authors.lastname: Nagaraj
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research Graz, Austria.
authors.forename: Bakytbek
authors.initials: B
authors.lastname: Egemnazarov
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular ResearchGraz, Austria; Institute of Physiology, Medical University of GrazGraz, Austria.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz Graz, Austria.
authors.forename: Rudolf E
authors.initials: RE
authors.lastname: Stauber
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular ResearchGraz, Austria; Institute for Medical Informatics, Statistics and Documentation, Medical University of GrazGraz, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Avian
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Medical University of GrazGraz, Austria; Ludwig Boltzmann Institute for Lung Vascular ResearchGraz, Austria.
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular ResearchGraz, Austria; Institute of Physiology, Medical University of GrazGraz, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
keywords: ABC transporters; diastolic dysfunction; hypoxia; pulmonary hypertension; right ventricular function; ventricular fibrosis