Abstract 5056: Genetic Disruption of the ATP-binding Cassette Transporter BCRP1/ABCG2 Impairs Cardiac Repair After Myocardial Infarction

Abstract

Introduction Recently, the ATP-binding cassette transporter BCRP1/ABCG2 has been shown to regulate the function and survival of side population cells, which have been identified in various organs including heart and have stem cell properties. In addition, previous studies have revealed that BCRP1/ABCG2 is also expressed in endothelial cells of capillaries and arterioles in heart. This study was performed to clarify the role of BCRP1/ABCG2 in cardiac repair after myocardial infarction (MI). Methods and Results MI was induced in 8- to 12-week-old wild-type (WT) mice (n=51) and Bcrp1/Abcg2 knock-out (KO) mice (n=60) by ligating the left anterior descending artery. At 28 days after MI, the survival rate was significantly lower in KO mice than in WT mice (28.3% versus 74.5%, p=0.0001). The main cause of death in KO mice was cardiac rupture (CR) (67.4%), whereas CR was observed in only 30.8% among WT mice (p=0.019). Echocardiography showed that ventricular remodeling was more deteriorated in KO mice than in WT mice (left ventricular end-diastolic diameter, 5.16±0.31 mm versus 4.47±0.30 mm, p<0.05; ejection fraction, 23.8±4.9% versus 32.9±5.8%, p=0.002), although baseline data did not differ between the two groups. The left ventricular end-diastolic pressure was more elevated in KO mice than in WT mice (10.7±4.1 mmHg versus 5.3±3.0 mmHg, p=0.006). Histological assessment revealed that myocyte hypertrophy and fibrosis in the non-infarcted area were exacerbated in KO mice compared with those in WT mice (myocyte cross-sectional area, 397.6±44.9 μ m 2 versus 312.7±27.1 μ m 2 , p<0.05; collagen volume fraction, 3.8±1.2% versus 2.2±0.7%, p=0.008). Capillary density in the peri-infarction area at 5 days after MI was significantly reduced in KO mice than in WT mice as determined by anti-CD31 immunostaining (1033±188/mm 2 versus 1414±214/mm 2 , p=0.008). The number of macrophages (MΦs) and myofibroblasts (MFs), as identified by immunostaining for Mac-3 and α -SMA respectively, also decreased in KO mice than in WT mice (MΦs, 1359±251/mm 2 versus 1906±440/mm 2 , p=0.04; MFs, 1780±479/mm 2 versus 2582±330/mm 2 , p=0.007). Conclusions Cardiac repair after MI was impaired in KO mice. BCRP1/ABCG2 may play an important role in angiogenesis and in recruitment of MΦs and MFs after MI.