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 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.
Objective— To clarify the impact of breast cancer resistance protein 1 (BCRP1)/ATP-binding cassette transporter subfamily G member 2 (ABCG2) expression on cardiac repair after myocardial infarction (MI). Methods and Results— The ATP-binding cassette transporter BCRP1/ABCG2 is expressed in various organs, including the heart, and may regulate several tissue defense mechanisms. 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 knockout (KO) mice 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 because of cardiac rupture. Echocardiographic, hemodynamic, and histological assessments showed that ventricular remodeling was more deteriorated in KO than in WT mice. Capillary, myofibroblast, and macrophage densities in the peri-infarction area at 5 days after MI were significantly reduced in KO compared with WT mice. In vitro experiments demonstrated that inhibition of BCRP1/ABCG2 resulted in accumulation of intracellular protoporphyrin IX and impaired survival of microvascular endothelial cells under oxidative stress. Moreover, BCRP1/ABCG2 inhibition impaired migration and tube formation of endothelial cells. Conclusion— BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function.
Objective— ATP-binding cassette transporter subfamily G member 2 (ABCG2), expressed in microvascular endothelial cells in the heart, has been suggested to regulate several tissue defense mechanisms. This study was performed to elucidate its role in pressure overload–induced cardiac hypertrophy. Methods and Results— Pressure overload was induced in 8- to 12-week-old wild-type and Abcg2 −/− mice by transverse aortic constriction (TAC). Abcg2 −/− mice showed exaggerated cardiac hypertrophy and ventricular remodeling after TAC compared with wild-type mice. In the early phase after TAC, functional impairment in angiogenesis and antioxidant response in myocardium was found in Abcg2 −/− mice. In vitro experiments demonstrated that ABCG2 regulates transport of glutathione, an important endogenous antioxidant, from microvascular endothelial cells. Besides, glutathione transported from microvascular endothelial cells in ABCG2-dependent manner ameliorated oxidative stress–induced cardiomyocyte hypertrophy. In vivo, glutathione levels in plasma and the heart were increased in wild-type mice but not in Abcg2 −/− mice after TAC. Treatment with the superoxide dismutase mimetic ameliorated cardiac hypertrophy in Abcg2 −/− mice after TAC to the same extent as that in wild-type mice, although cardiac dysfunction with impaired angiogenesis was observed in Abcg2 −/− mice. Conclusion— ABCG2 protects against pressure overload–induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.
Lymphocyte activation is thought to play a major role in the pathogenesis of atherosclerotic complications such as plaque thrombosis. Circulating CD31+ T cells have been shown to regulate human T cell activation. Aim of this study was to evaluate whether the proportion of circulating immunoregulatory CD31+ T cells is correlated to the occurrence of plaque thrombosis in aged apolipoprotein (apo) E knockout (KO) mice.CD31+ T cell depletion of spleen T cells enhanced proliferation (P<0.05) and interferon-gamma production (P<0.01) while reducing interleukin (IL)-4 (P<0.001) and IL-10 (P=0.001) secretion in response to minimally modified low-density lipoprotein. CD31+ T cells were counted in 65 apoE KO mice (46-week-old) by flow cytometry. Organizing thrombi could be documented in 28 of 195 (14%) lesions and in at least one of the aorta root lesions in 23 of 65 mice (35%). CD31+ T cell count was significantly reduced in mice showing plaque thrombosis (72.3+/-1.5% versus 84.1+/-1.2%; P<0.0001), but such reduction did not follow induced plaque rupture or experimentally controlled thrombosis.Reduced CD31+ T cells in circulating blood is a hallmark of atherosclerotic plaque thrombosis. Our data suggest that CD31+ T cells may play an important regulatory role in the development of plaque thrombosis.
Objective— Circulating progenitors and stem cells have been reported to contribute to angiogenesis and arterial repair after injury. In the present study, we investigated whether the arterial wall could host permanently residing progenitor cells under physiological context. Methods and Results— Using the Hoechst-based flow cytometry method, we identified and isolated progenitor cells termed side population (SP) cells at a prevalence of 6.0±0.8% in the tunica media of adult mice aortas. Arterial SP cells expressed the ATP-binding cassette transporter subfamily G member 2, frequently present on SP cell surface, and displayed a Sca-1 + c-kit −/low Lin − CD34 −/low profile. They did not form myeloid or lymphoid hematopoietic colonies after plating in methylcellulose-based medium. Importantly, cultured SP cells were able to acquire the phenotype of endothelial cells (CD31, VE-cadherin, and von Willebrand factor expression) or of smooth muscle cells (α-smooth muscle actin, calponin, and smooth muscle myosin heavy chain expression), in presence of either vascular endothelial growth factor or transforming growth factor (TGF)-β1/PDGF-BB, respectively. Moreover, they generated vascular-like branching structures, composed of both VE-cadherin + cells and α-smooth muscle actin + cells on Matrigel. Conclusions— In this study, we provide the first evidence to our knowledge that in the adult mice, the normal arterial wall harbors SP cells with vascular progenitor properties.
