Abstract 9111: The ATP-binding Cassette Transporter BCRP1/ABCG2 Plays a Pivotal Role in Cardiac Repair After Myocardial Infarction via Modulation of Microvascular Endothelial Cell Survival and Function
Background: The ATP-binding cassette transporter BCRP1/ABCG2 has been shown to be expressed in various normal organs including the heart, and has been suggested to regulate several tissue defense mechanisms via modulation of survival and function of BCRP1/ABCG2-expressing cells besides active efflux of toxins. However, its physiological significance in cardiac repair after myocardial infarction (MI) remains unknown.
Methods and Results: Immunohistochemistry showed that BCRP1/ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. MI was induced in 8- to 12-week-old wild-type (WT) and Bcrp1/Abcg2 knock-out (KO) mice by ligating the left anterior descending artery. In the absence of MI, cardiac function and morphology did not differ between WT and KO mice. At 28 days after MI, survival rate was significantly lower in KO mice than in WT mice mainly due to cardiac rupture (28.3%, n=60, versus 74.5%, n=51, p<0.0001). Echocardiographic, hemodynamic and histological assessments showed that ventricular remodeling was more deteriorated in KO mice than in WT mice. Capillary, myofibroblasts and macrophages density in the peri-infarction area at 5 days after MI were significantly reduced in KO mice compared with WT mice, although gene expression of angiogenesis-related, fibrosis-related and pro-inflammatory cytokines was comparable or higher in KO mice than in WT mice. In vitro experiments revealed that inhibition of BCRP1/ABCG2 resulted in accumulation of intra-cellular protoporphyrin IX (PPIX) in human microvascular endothelial cells from the heart (HMVEC-Cs), which may exaggerate oxidative stress, and impaired survival of HMVEC-Cs under oxidative stress. In fact, the PPIX level in the heart was higher in KO mice than in WT mice, and oxidative stress in the peri-infarction area at 5 days after MI was exaggerated in KO mice compared with that in WT mice. Moreover, in vitro experiments showed that BCRP1/ABCG2 inhibition led to impaired migration and tube formation of HMVEC-Cs even under normal condition.
Conclusions: BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function. BCRP1/ABCG2 might be of interest for a therapeutic target to improve post-MI outcomes.
- © 2010 by American Heart Association, Inc.