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
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.
Breast cancer resistance protein 1 (BCRP1)/ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a member of the ATP-binding cassette transporter family originally identified by its ability to confer drug resistance in tumor cells by active efflux of multiple drugs.1 This protein is expressed in various healthy organs and protects organs against toxic compounds and their metabolites.2 In addition, previous in vitro experiments demonstrated that BCRP1/ABCG2 provides an important cell survival advantage under hypoxia or oxidative stress.3,4 Moreover, recent studies5,6 revealed that BCRP1/ABCG2-expressing cells include tissue progenitor cells and that BCRP1/ABCG2 plays a pivotal role in modulating the proliferation, differentiation, and survival of these cells. These results suggested that BCRP1/ABCG2 regulates several tissue defense mechanisms in various organs.7
In the heart, BCRP1/ABCG2 was mainly expressed in the endothelial cells of microvessels,8,9 which, together with fibroblasts, compose most noncardiomyocytes. In addition, BCRP1/ABCG2-expressing cardiac progenitor cells may exist, although the number is small.8,10–12 Other studies9,13 suggested that BCRP1/ABCG2 may have functions in tissue defense in the diseased heart. However, the physiological significance of BCRP1/ABCG2 expression in cardiac injury has not yet been fully elucidated. This study was performed to clarify the impact of BCRP1/ABCG2 expression on cardiac repair after myocardial infarction (MI).
Experimental Model of MI
This study was approved by the Animal Care and Use Committee of the University of Tokyo, Tokyo, Japan. All experiments were performed according to the Guide for the Care and Use of Laboratory Animals.14 Female wild-type (WT) FVB/NJcl mice, aged 8 to 12 weeks (CLEA Japan, Hamamatsu, Japan), and Bcrp1/Abcg2 knockout (KO) mice (FVB/N background; model 2767-F; TACONIC, Hudson, NY) were used.15 WT mice originated from the National Institutes of Health, Bethesda, MD; and have been bred in CLEA Japan since 1993. Thus, the genetic background of FVB/NJcl mice is the same as that of FVB/NTac mice (TACONIC). In our preliminary experiments, no potential difference was found between the 2 groups (supplemental Figure I; available online at http://atvb.ahajournals.org). KO mice were established in the laboratory of Alfred H. Schinkel, PhD, and colleagues at the Netherlands Cancer Institute15 and were backcrossed to FVB/N mice for 7 generations. A permanent left anterior descending artery ligation was performed as previously described. (Additional information is provided in the supplemental data).16
Echocardiographic and Hemodynamic Measurements
A transthoracic echocardiographic study was performed under anesthesia with sodium pentobarbital before surgery and at 28 days after MI with a dynamically focused 15-MHz linear-array transducer (EnVisor M2540A). For hemodynamic measurement, the right carotid artery was cannulated by the micropressure transducers (supplemental data).
Mice were euthanized at baseline and at 5 and 28 days after MI. Hearts were weighed, fixed in methanol, and cut into 4 transverse sections: apical, middle, upper, and basal. Each part was embedded in paraffin and sectioned at a 5-μm thickness. Histological analysis was performed as previously described (supplemental data).16
RNA Extraction and RT-PCR Analysis
Total RNA was isolated from the myocardial tissues of the peri-infarction area and cultured cells with reagent (TRIzol Reagent) and an RNA isolation kit, respectively. Reverse transcription was performed with 1 μg of total RNA, random hexamer primers, and Moloney murine leukemia virus reverse transcriptase (ReverTraAce-α).17 For quantitative assessment of gene expression levels, quantitative real-time PCR analysis was performed (supplemental data).
Human microvascular endothelial cells from the heart (HMVEC-Cs) were purchased. Cell viability was measured by dimethylthiazol-carboxymethoxyphenyl-sulfophenyl-tetrazolium assay. The intracellular protoporphyrin IX concentration in HMVEC-Cs was measured as previously described.3 Migration and tube formation assays were performed using a commercially available system (BD BioCoat Angiogenesis System) according to the manufacturer’s guidelines (supplemental data).
Measurement of Protoporphyrin IX Concentration and Oxidative Stress in Murine Heart
The concentration of protoporphyrin IX, including heme in murine hearts, was measured as previously described.18 For assessment of oxidative stress in murine hearts, lipid peroxidation and protein oxidation were measured according to the manufacturer’s recommendation (supplemental data).
Data are expressed as mean±SEM. The Kaplan-Meier method and the log-rank test were used for comparison of survival. Comparison between 2 groups was analyzed by the 2-tailed Student t test. The paired t test was used to compare echocardiographic parameters before and 28 days after MI. Frequencies were compared with the Fisher exact probability test. A multiple group comparison was performed by 1-way ANOVA, followed by the Bonferroni procedure, for comparison of means. P<0.05 was considered statistically significant.
Expression of BCRP1/ABCG2 in the Heart
BCRP1/ABCG2 is abundantly expressed in proximal tubule cells of murine kidney.19,20 By using a kidney specimen as a positive control, we identified the expression of BCRP1/ABCG2 mRNA in murine heart by conventional RT-PCR (Figure 1A). Immunohistochemical staining of the heart from WT mice with anti-BCRP1/ABCG2 antibody demonstrated that BCRP1/ABCG2 was mainly expressed in the endothelial cells of microvessels (Figure 1B).
Mortality in WT and KO Mice After MI
The survival rate up to 28 days after MI was significantly lower in KO than in WT mice (28.3% [n=60] versus 74.5% [n=51]; P<0.0001) (Figure 2A), whereas all of the sham-operated WT and KO mice survived until 28 days after MI (n=10 for each group). The main cause of death in KO mice was cardiac rupture in 4 to 6 days after MI, which was identified by the presence of intrathoracic hematoma. Cardiac rupture occurred more often in KO than in WT mice (67.4% versus 30.8%; P=0.02).
Echocardiography and Hemodynamics
Left ventricular dimensions and function, examined using echocardiography, were similar in WT and KO mice before MI (Figure 2B and supplemental Table). However, at 28 days after MI, left ventricle (LV) dilatation and thickening of the noninfarcted area were worse in KO than in WT mice. In addition, ejection fraction was more decreased in KO than in WT mice. These results indicated that ventricular remodeling after MI was exaggerated in KO compared with WT mice. There was no significant difference in aortic blood pressure, left ventricle end-diastolic pressure (LVEDP), maximum +dP/dt (+dP/dtmax), and maximum −dP/dt (−dP/dtmax) between WT and KO mice at baseline (Figure 2C and supplemental Table). At 28 days after MI, LVEDP, +dP/dtmax, and −dP/dtmax were more deteriorated in KO compared with WT mice. There was no significant difference between sham-operated WT and KO mice in echocardiographic and hemodynamic data.
Heart Weight:Body Weight Ratio and Infarct Size
Heart weight:body weight ratio did not differ between the 2 groups at baseline (Figure 2D). However, at 28 days after MI, heart weight:body weight ratio was greater in KO than in WT mice. In sham-operated mice, there was no significant difference in heart weight:body weight ratio between the 2 groups. Initial area at risk and initial infarct size did not differ between the 2 groups (supplemental Figure II), whereas infarct size at 28 days after MI was significantly larger in KO than in WT mice (Figure 2E).
Myocyte Cross-Sectional Area and Collagen Volume Fraction in the Noninfarcted Area
At baseline, myocyte cross-sectional area (CSA) and collagen volume fraction (CVF) did not differ between WT and KO mice (supplemental Figure III and supplemental Figure IV). At 28 days after left anterior descending artery occlusion, myocyte CSA and CVF in noninfarcted area were greater in KO than in WT mice, which indicated exacerbated ventricular remodeling in KO mice. There was no significant difference between sham-operated WT and KO mice in myocyte colony-stimulating activity and CVF.
Capillary Density and Diameter in the Peri-Infarction Area
At baseline, LV capillary density and diameter did not differ between WT and KO mice (Figure 3A). At 5 days after MI, the capillary density in the peri-infarction area was lower in KO than in WT mice. At 28 days after MI, capillary density remained significantly lower in KO than in WT mice. In addition, capillary diameter in the peri-infarction area was smaller in KO than in WT mice at 5 and 28 days after MI. Thus, mature vessel formation was impaired in KO mice.
Macrophage and Myofibroblast Infiltrations in the Peri-Infarction Area
At baseline, we rarely found macrophages and myofibroblasts in both WT and KO mice. At 5 days after MI, the numbers of macrophages and myofibroblasts were significantly lower in KO than in WT mice (Figure 3B and C).
Cytokine mRNA Expression in the Peri-Infarction Area
At baseline, cytokine mRNA expression levels were comparable between WT and KO mice (Figure 4). Gene expression levels of tumor necrosis factor α were comparable between WT and KO mice even after MI; the expression of interleukin 6 and monocyte chemotactic protein-1 (MCP-1), other proinflammatory cytokines, was more exaggerated in KO than in WT mice at 5 days after MI. The expression level of matrix metalloproteinase-9 was also higher in KO than in WT mice at 5 days after MI. When we compared angiogenesis-related genes, the expression levels of hypoxia-inducible factor (HIF)-2α and angiopoietin-1 were higher in KO than in WT mice at 5 days after MI; the expression levels of HIF-1α and vascular endothelial growth factor A were comparable between the 2 groups. At 28 days after MI, the expression level of angiopoietin-1 was still higher in KO than in WT mice, although vascular endothelial growth factor A was more expressed in WT than in KO mice. The expression levels of fibrosis-related genes, such as transforming growth factor (TGF)-β1, fibronectin, collagen type 1, alpha 1 (COL1A1), and collagen type 3, alpha 1 (COL3A1), were comparable between WT and KO mice at 28 days after MI. However, at 5 days after MI, TGF-β1, fibronectin, and COL1A1 were more expressed in KO than in WT mice.
Impact of BCRP1/ABCG2 on Survival of Microvascular Endothelial Cells Under Hypoxia and Oxidative Stress
Survival of microvascular endothelial cells under hypoxia or oxidative stress is important for angiogenesis after MI. We assessed the impact of BCRP1/ABCG2 expression in microvascular endothelial cells of the heart on their survival by using HMVEC-Cs. The expression of BCRP1/ABCG2 in HMVEC-Cs was identified by conventional RT-PCR (Figure 5A). The inhibition of BCRP1/ABCG2 by fumitremorgin c (FTC) did not alter the cell viability of HMVEC-Cs under normal conditions. However, under oxidative stress with 200-μmol/L hydrogen peroxide, the cell viability of HMVEC-Cs with FTC was more impaired than that without FTC (Figure 5B). Under hypoxia, no significant difference was found in the cell viability between HMVEC-Cs with and without FTC.
Impact of BCRP1/ABCG2 Inhibition on Intracellular Protoporphyrin IX Concentration in HMVEC-Cs
The regulation of porphyrins and heme within a cell is important for cellular defense against oxidative stress.21–23 Recent data3 suggested that BCRP1/ABCG2 plays an important role in intracellular protoporphyrin IX concentration by active efflux. Flow cytometry analysis demonstrated that protoporphyrin IX concentration was higher in HMVEC-Cs with FTC than in those without FTC (Figure 5C), which indicated that BCRP1/ABCG2 plays an important role in the efflux of intracellular protoporphyrin IX in microvascular endothelial cells of the heart in normal expression level.
Protoporphyrin IX Level and Oxidative Stress In Vivo
The levels of protoporphyrin IX, including heme in the heart, were higher in KO than in WT mice (Figure 5D), although serum bilirubin levels did not differ between the 2 groups in our breeding environment (0.79±0.07 versus 0.75±0.09 mol/L; P=0.77). Lipid peroxidation assay and oxyblot analysis demonstrated that oxidative stress in the peri-infarction area at 5 days after MI was exaggerated in KO compared with WT mice, although there was no significant difference between the 2 groups at baseline and at 28 days after MI (Figure 5E and F).
Impact of BCRP1/ABCG2 on Function of Microvascular Endothelial Cells
For assessment of the function of HMVEC-Cs, gene expressions of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial NO synthase under inflammatory conditions and migration and tube formation properties were examined. Real-time PCR showed that inhibition of BCRP1/ABCG2 did not alter the expression pattern of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial NO synthase even under oxidative stress in HMVEC-Cs (Figure 6A). However, pharmacological inhibition of BCRP1/ABCG2 impaired migration and tube formation of HMVEC-Cs under both normal and oxidative stress conditions (Figure 6B-D).
In the present study, we found that BCRP1/ABCG2 is expressed mainly in the endothelial cells of microvessels in the heart. We also demonstrated that genetic disruption of BCRP1/ABCG2 deteriorated mortality and cardiac remodeling after MI. In KO mice, angiogenesis and recruitment of macrophages and myofibroblasts were impaired. In vitro experiments showed that BCRP1/ABCG2 played an important role in survival of microvascular endothelial cells of the heart under oxidative stress, possibly, at least in part, by preventing the accumulation of intracellular protoporphyrin IX. In addition, we found that BCRP1/ABCG2 have effects on migration and tube formation of microvascular endothelial cells of the heart.
The cardiac healing process after MI was divided into 3 overlapping phases: inflammatory, proliferative, and maturation.24 Because most deaths in KO mice occurred in 4 to 6 days after MI, we assessed the healing process at 5 days after MI, which is under the proliferative phase. During the proliferative phase of healing, fibroblasts and endothelial cells activated by cytokines and growth factors proliferate, leading to the formation of highly vascularized granulation tissue. In addition, activated myofibroblasts produce extracellular matrix proteins and an extensive microvascular network is formed.
Because BCRP1/ABCG2 is expressed mainly in endothelial cells of microvessels, we first assessed angiogenesis. At 5 days after MI, mature vessel formation was impaired in KO compared with WT mice, although the expression levels of angiogenesis-related cytokines were comparable or higher in KO than in WT mice. Previous studies3,4 showed that BCRP1/ABCG2 played an important role in cell survival under hypoxia or oxidative stress, which is induced in ischemic conditions and exaggerates cardiac injury.25 In our in vitro experiments, we found that BCRP1/ABCG2 is essential for survival of microvascular endothelial cells of the heart under oxidative stress, which is important for angiogenesis in damaged tissues.
Previous studies3,15 suggested the mechanisms by which BCRP1/ABCG2 expression protect cell death. BCRP1/ABCG2 may cause effluxion of protoporphyrin IX. The regulation of porphyrins and heme within a cell is important because the accumulation of heme within a cell can ultimately lead to the accumulation of iron and the production of cell-damaging reactive oxygen species by the Fenton reaction.21–23 In our in vitro experiments, we found that BCRP1/ABCG2 inhibition leads to accumulation of protoporphyrin IX in microvascular endothelial cells of the heart. This result may explain why inhibition of BCRP1/ABCG2 led to impaired survival of microvascular endothelial cells under oxidative stress but not under normal conditions. In fact, we demonstrated that the protoporphyrin IX level in the heart was higher in KO than in WT mice. In addition, oxidative stress in the peri-infarction area was exaggerated in KO versus WT mice at 5 days after MI, although there was no significant difference at baseline between the 2 groups. These results support our hypothesis that elevated protoporphyrin IX levels in microvascular endothelial cells may result in exaggeration of oxidative stress and, thus, lead to impaired angiogenesis under oxidative stress in KO mice.
During angiogenesis, not only cell survival, but also migration and tube formation of endothelial cells are essential. In the present study, we found that pharmacological inhibition of BCRP1/ABCG2 resulted in impaired migration and tube formation of HMVEC-Cs, even under normal conditions. These results suggest that BCRP1/ABCG2 may also play an important role in chemotaxis of microvascular endothelial cells. Therefore, impaired survival under oxidative stress and impaired chemotaxis of microvascular endothelial cells might lead to impaired mature vessel formation in KO mice. Impaired angiogenesis might result in delayed cardiac repair after MI and then exaggerated expression of proinflammatory signals in KO mice, which was supported by exacerbated expression of interleukin 6.
In the present study, macrophage recruitment was also impaired in KO mice at 5 days after MI, although the expression level of MCP-1 was higher in KO than in WT mice. The previous study15 showed that loss of BCRP1/ABCG2 does not affect hematopoiesis. In addition, our in vitro experiments showed that BCRP1/ABCG2 had no effect on expression of adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 or endothelial NO synthase in microvascular endothelial cells under inflammatory conditions, even with oxidative stress. Therefore, impaired angiogenesis might lead to impaired macrophage recruitment from the bloodstream. Because macrophages play an important role in clearance of necrotic cardiomyocytes, impaired macrophage recruitment might contribute to impaired cardiac healing and fragility of myocardium.
In this study, the number of myofibroblasts was reduced in KO compared with WT mice at 5 days after MI. Myofibroblasts have been thought to derive from resident fibroblasts. However, our data showed that TGF-β1, a cytokine that induces differentiation of fibroblasts into myofibroblasts,26 was highly expressed in KO mice. In addition, COL1A1 and fibronectin expressions were higher in KO than in WT mice. These results appear discrepant between fibroblast activity and myofibroblast recruitment. However, TGF-β is a pleiotropic and multifunctional cytokine, known to exert diverse and often contradictory cellular effects on all cell types.27 TGF-β–mediated actions are not only dependent on cell type but also on its stage of differentiation and on the cytokine milieu. Thus, impaired cytokine balance by impaired angiogenesis may explain this discrepancy.
Because myofibroblasts play a pivotal role in wound strengthening in the healing process, impaired recruitment of myofibroblasts, together with exaggerated expression of matrix metalloproteinases and impaired clearance of necrotic cardiomyocytes by macrophages, may explain why cardiac rupture was more often observed in KO mice in 4 to 6 days after MI. In fact, when we compared specimens of mice that died of cardiac rupture at 5 days after MI, granulation tissue formation was impaired in KO compared with WT mice (supplemental Figure V). In addition, the augmented fragility of myocardium in the early stage of cardiac healing might lead to excessive infarct expansion and then to exaggerated infarct size and ventricular remodeling at 28 days after MI in KO compared with WT mice, together with exaggerated expression of proinflammatory signals and fibrosis-related cytokines.
In previous studies, BCRP1/ABCG2-expressing cardiac progenitor cells had the potential to differentiate into cardiomyocyte-like cells and endothelial-like cells in vivo after cardiac injury.8,11 However, the number of these cells is extremely small. In addition, the contribution of these cells to cardiac repair after MI remains controversial.28–30 The significance of these cells and impact of BCRP1/ABCG2 expression through regulating function of these cells in cardiac healing after MI must be elucidated in further studies.
Our findings suggest that upregulation of BCRP1/ABCG2 expression may improve the cardiac healing process after MI and post-MI outcomes. In the previous study,31 a peroxisome proliferator–activated receptor γ agonist regulated Bcrp1/Abcg2 expression positively. Shiomi et al32 demonstrated that pioglitazone ameliorates ventricular remodeling after MI in mice. Upregulation of BCRP1/ABCG2 might, at least in part, contribute to this result. The development of drugs that upregulate BCRP1/ABCG effectively appears to be promising.
In conclusion, we demonstrated that BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function. Our results suggest that BCRP1/ABCG2 may be of interest for a therapeutic target to improve clinical outcomes after MI.
Sources of Funding
This study was supported in part by the Program for Promotion of Basic and Applied Researches for Innovations in Bio-oriented Industry; a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a grant from the Ministry of Health, Labor and Welfare of Japan.
This manuscript was sent to Linda Demer, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received on: June 24, 2010; final version accepted on: August 22, 2010.
Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A. 1998; 95: 15665–15670.
Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, Sorrentino BP, Schuetz JD. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004; 279: 24218–24225.
Martin CM, Ferdous A, Gallardo T, Humphries C, Sadek H, Caprioli A, Garcia JA, Szweda LI, Garry MG, Garry DJ. Hypoxia-inducible factor-2alpha transactivates Abcg2 and promotes cytoprotection in cardiac side population cells. Circ Res. 2008; 102: 1075–1081.
Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001; 7: 1028–1034.
Pfister O, Oikonomopoulos A, Sereti KI, Sohn RL, Cullen D, Fine GC, Mouquet F, Westerman K, Liao R. Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. Circ Res. 2008; 103: 825–835.
Huls M, Russel FG, Masereeuw R. The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther. 2009; 328: 3–9.
Oyama T, Nagai T, Wada H, Naito AT, Matsuura K, Iwanaga K, Takahashi T, Goto M, Mikami Y, Yasuda N, Akazawa H, Uezumi A, Takeda S, Komuro I. Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J Cell Biol. 2007; 176: 329–341.
Meissner K, Heydrich B, Jedlitschky G, Meyer Zu, Schwabedissen H, Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Bohm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK. The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart. J Histochem Cytochem. 2006; 54: 215–221.
Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, Colucci WS, Liao R. CD31− but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res. 2005; 97: 52–61.
Institute of Laboratory Animal Resources, US Committee on Care and Use of Laboratory Animals, US National Institutes of Health. Guide for the Care and Use of Laboratory Animals. Bethesda, MD: US Dept of Health and Human Services, Public Health Service, National Institutes of Health; 1985.
Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plosch T, Kuipers F, Elferink RP, Rosing H, Beijnen JH, Schinkel AH. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 2002; 99: 15649–15654.
Nakamura K, Sata M, Iwata H, Sakai Y, Hirata Y, Kugiyama K, Nagai R. A synthetic small molecule, ONO-1301, enhances endogenous growth factor expression and augments angiogenesis in the ischaemic heart. Clin Sci (Lond). 2007; 112: 607–616.
Shoji M, Sata M, Fukuda D, Tanaka K, Sato T, Iso Y, Shibata M, Suzuki H, Koba S, Geshi E, Katagiri T. Temporal and spatial characterization of cellular constituents during neointimal hyperplasia after vascular injury: potential contribution of bone-marrow-derived progenitors to arterial remodeling. Cardiovasc Pathol. 2004; 13: 306–312.
Sassa S. Sequential induction of heme pathway enzymes during erythroid differentiation of mouse Friend leukemia virus-infected cells. J Exp Med. 1976; 143: 305–315.
Liu X, Pachori AS, Ward CA, Davis JP, Gnecchi M, Kong D, Zhang L, Murduck J, Yet SF, Perrella MA, Pratt RE, Dzau VJ, Melo LG. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J. 2006; 20: 207–216.
Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993; 122: 103–111.
Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007; 74: 184–195.
Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004; 428: 664–668.
Szatmari I, Vamosi G, Brazda P, Balint BL, Benko S, Szeles L, Jeney V, Ozvegy-Laczka C, Szanto A, Barta E, Balla J, Sarkadi B, Nagy L. Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem. 2006; 281: 23812–23823.
Shiomi T, Tsutsui H, Hayashidani S, Suematsu N, Ikeuchi M, Wen J, Ishibashi M, Kubota T, Egashira K, Takeshita A. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002; 106: 3126–3132.