Abstract 17865: Right Ventricular Diastolic Dysfunction in ABCG2 knockout mice under Hypoxia
Introduction: Right ventricular (RV) hypertrophy followed by RV dysfunction is the main cause of mortality in pulmonary hypertension (PH). The protective role of the inhibition of ABCC4 membrane transporter in pulmonary vascular remodeling has been recently shown. However, our knowledge about the expression of other ABC membrane transporters in the pulmonary vasculature and their role in PH and RV function is limited.
Aim: The current study addresses the role of ABCG2 transporter in the right ventricular function in the well established hypoxia-induced PH murine model.
Methods: Expression studies have been carried out on lung samples obtained from patients with idiopathic pulmonary arterial hypertension and from healthy controls.
Age- and sex-matched WT (n≥9) and ABCG2 knockout (n≥9) male mice were housed in normoxic (21% O2) and hypoxic (10% O2) environment for total of 4 weeks. Hemodynamic parameters such as RV systolic pressure, left ventricular systolic pressure and blood pressure were assessed by catheterisation. Harvested lung and heart tissues were characterised by immunohistochemistry.
Results: Hypoxia induced pulmonary vascular remodeling, RV systolic pressure elevation and RV hypertrophy in WT animals. RV end-diastolic pressure (RVEDP) was also increased in WT animals under hypoxia as compared to the normoxic group (3.3 ± 0.1mmHg vs. 1.7 ± 0.1mmHg, p <0.001). In hypoxia, ABCG2 knockout mice showed pulmonary vascular remodeling, RV systolic pressure elevation and RV hypertrophy in the same extent as it was observed in the WT group. However, loss of ABCG2 significantly elevated the RVEDP after hypoxic exposure compared to WT controls (4.9 ± 0.2mmHg vs. 3.3 ± 0.1mmHg, p <0.001) with preserved systolic- and left ventricular function. To further elucidate the role of ABCG2 in the observed phenotype, collagen content and capillary density quantification was performed on RV heart sections. Under hypoxia ABCG2 knockout mice showed markedly increased fibrosis as compared to WT counterparts (1,3 ± 0,2% vs. 0,6 ± 0,2%, p <0.05) without altered capillary density in the RV.
Conclusions: Loss of ABCG2 results in increased myocardial fibrosis in right ventricle under hypoxia. This may partly lead to an elevated RVEDP causing more severe diastolic dysfunction.
- © 2013 by American Heart Association, Inc.