Abstract 9918: The ATP-Binding Cassette Transporter ABCG2 Protects Against Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Promoting Angiogenesis and Antioxidant Response

Abstract

Background: ATP-binding cassette transporter subfamily G member 2 (ABCG2), originally identified in cancer cells, was shown to be expressed in various normal organs, including the heart, and was suggested to regulate several tissue defense mechanisms via modulation of survival and function of ABCG2-expressing cells. However, its role in pressure overload-induced cardiac hypertrophy remains unknown. Methods and Results: Immunohistochemistry demonstrated that ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. Pressure overload was induced in 8- to 12-week-old wild-type (WT) and Abcg2 knock-out (KO) mice by transverse aortic constriction (TAC). In the absence of pressure overload, cardiac function and morphology did not differ between WT and KO mice. In WT mice, ABCG2 mRNA expression was increased about 3 times at 4 days and 28 days after TAC compared with that before surgery. At 28 days after TAC, mortality due to heart failure was higher in KO mice than in WT mice (KO mice, 53.2%, n=62, versus WT mice, 21.2%, n=33, p=0.002). Most of dead KO mice died at 4 days after TAC. KO mice showed exaggerated concentric hypertrophy at 4 days after TAC, and exacerbated ventricular remodeling and impaired systolic function at 28 days after TAC compared with WT mice. At 4 days after TAC, impaired angiogenesis and exaggerated oxidative stress in myocardium were found in KO mice compared with those in WT mice, although expression levels of angiogenesis-related and antioxidant genes were comparable or higher in KO mice than in WT mice. In vitro experiments demonstrated that inhibition of ABCG2 led to impaired survival of human microvascular endothelial cells from the heart (HMVEC-Cs) under oxidative stress. In addition, ABCG2 inhibition resulted in impaired migration and tube formation of HMVEC-Cs even under normal condition. Moreover, ABCG2 regulated extracellular concentrations of glutathione, an important endogenous antioxidant, in HMVEC-Cs under external stimuli. Conclusions: ABCG2 protects against pressure overload-induced cardiac hypertrophy and subsequent heart failure by promoting angiogenesis and antioxidant response. ABCG2 may be of interest for a therapeutic target to improve clinical outcomes of hypertrophic heart disease.