Ann Thorac Surg 2006;82:657-663
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Human Coronary Microvascular Effects of Cardioplegia-Induced Stromal-Derived Factor-1
Shigetoshi Mieno, MDa,
Munir Boodhwani, MDa,
Basel Ramlawi, MDa,
Jianyi Li, MB, MSa,
Jun Feng, MD, PhDa,
Cesario Bianchi, MD, PhDa,
Roger J. Laham, MDa,
Jian Li, MD, PhDb,
Frank W. Sellke, MDa,*
a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts
b Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Accepted for publication March 15, 2006.
* Address correspondence to Dr Sellke, Division of Cardiothoracic Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, 110 Francis St, Suite 2A, Boston, MA 02215. (Email: fsellke{at}bidmc.harvard.edu).
 |
Abstract
|
|---|
BACKGROUND: Stromal-derived factor-1
(SDF-1) binds to its specific receptor, CXCR4, and plays an important role in ischemia-induced angiogenesis. Some of the effects of SDF-1 are likely due to effects on the microcirculation. Cardioplegia and cardiopulmonary bypass (CP/CPB) activate mitogen-activated protein kinase (MAPK) signaling pathways including p38, ERK1/2, and JNK. The purpose of the present study was to evaluate SDF-1 expression, and relationships between SDF-1-mediated coronary microvessel response and MAPKs.
METHODS: The atrial tissue of patients undergoing cardiac surgery was harvested before and after CP/CPB. Protein levels of SDF-1 and CXCR4 were measured by Western blot and immunohistochemistry, and plasma levels of SDF-1 were measured by enzyme-linked immunosorbent assay. Coronary microvessel responses to SDF-1 were assessed by videomicroscopy. To further elucidate SDF-1/CXCR4 signaling, microvessel responses were evaluated in the presence of CXCR4 antagonist (AMD3100) and MAPK inhibitors, ERK1/2 inhibitor (UO126), p38 inhibitor (SB203580), and JNK inhibitor (ALX-159-600).
RESULTS: Myocardial protein expression of SDF-1 was elevated after CP/CPB (9.5 ± 3.5-fold, p = 0.03 versus before CP/CPB). Increases in SDF-1 spatially localized to endothelial cells, smooth muscle cells, and myocytes. Plasma levels of SDF-1 were increased after CP/CPB (3.2 ± 2.8 versus 2.8 ± 1.7 ng /mL, p = 0.03 versus before CP/CPB). Stromal-derived factor-1 induced coronary microvessel contraction after CP/CPB (p = 0.046 versus before CP/CPB), which was blocked by the CXCR4 antagonist. Furthermore, SDF-1 induced microvessel contraction was inhibited by MAPK inhibitors, ERK-1/2 (p = 0.046), p38 (p = 0.049), and JNK inhibition (p = 0.06).
CONCLUSIONS: These results suggest that CP/CPB induces myocardial expression of SDF-1 and results in coronary microvessel contraction through MAPK signaling pathways.
|
Introduction
|
|---|
During cardiac surgery, cardioplegia and cardiopulmonary bypass (CP/CPB) causes ischemia-reperfusion injury resulting in altered expression of various cytokines. We, as well as others, have previously shown that the activity of mitogen-activated protein kinases (MAPK), including p38, ERK1/2, and JNK, are altered during CP/CPB [1, 2]. Furthermore, the expression of chemokines, such as CXCL2, CXCL3, CCL2, and CCL 4, increases in patients undergoing coronary artery bypass graft surgery after CP/CPB as demonstrated by gene-expression microarray analysis [3].
Stromal-derived factor-1 (SDF-1), a chemokine, is expressed and secreted from organs and tissues in response to ischemia [4, 5]. Stromal-derived factor-1 is the only ligand for CXCR4, which exists as a membrane receptor on mononuclear and endothelial cells [6]. The binding of SDF-1 to CXCR4 leads to the activation of several signal transduction pathways such as MEK kinase-MAPK p42/44 and PI3K-AKT-NF
B [7, 8]. The SDF-1/CXCR4 interaction plays a crucial role in endothelial progenitor cell trafficking, cell migration, and angiogenesis [9].
The use of bone marrow–derived progenitor cells for the treatment of myocardial ischemia hold great promise. Bone marrow mononuclear cells have been injected in patients with ischemic disease after myocardial infarction as well as in the setting of coronary artery bypass grafting [10–12]. Recent animal experiments demonstrated that SDF-1/CXCR4 interactions play a crucial role in the endogenous recruitment of bone marrow mononuclear cells to the heart after myocardial infarction and can further increase homing in the presence of SDF-1 [4]. Furthermore, it is well established that endothelial cells play an important role as a first step in cell homing for angiogenesis [13]. Thus, it is plausible that increased expression of SDF-1 after ischemia may have functional effects on the endothelium that subsequently induce the recruitment and homing of progenitor cells to areas of injury. However, little is known about the effects of SDF-1/CXCR4 on the endothelium in patients undergoing cardiac surgery with CP/CPB.
In this study, we examined the effect of CP/CPB on protein expression of SDF-1 and CXCR4 in atrial tissue and plasma obtained from patients before and after CP/CPB, as well as coronary microvascular response to SDF-1 before and after CP/CPB. In addition, we examined the contribution of MAPK signaling pathways responsible for the microvessel response induced by SDF-1.
|
Material and Methods
|
|---|
Human Subjects and Tissue Samples
The study was approved by the Institutional Review Board of Beth Israel Deaconess Medical Center, Harvard Medical School. Informed consent was obtained from patients enrolled in the study as required by the Institutional Review Board. Tissues were taken before CPB from the right atrial appendage at the time of venous cannulation. Two concentric venous pursestring sutures were placed on the right artial appendage, and the upper pursestring was used to secure the venous cannula. After CPB, atrial specimens were harvested at the time of decannulation between the two pursestring sutures on the right atrial appendage so that subsequent studies would assess the effects of CP/CPB and not just tissue ischemia. Tissue samples were immediately frozen in liquid nitrogen for Western blot analysis, or fixed in 10% formalin for immunohistochemistry, or placed in cold (5°C to 10°C) Krebs buffer solution for in-vitro microvessel studies. Blood was obtained from the patients before CPB and after CPB.
Western Blot Analysis
Whole-cell lysates were isolated from the atrial tissue taken from before and after CP/CPB (n = 6) with a RIPA buffer (Boston Bioproducts, Worcester, Massachusetts) and centrifuged at 12,000g for 10 minutes at 4°C to separate soluble from insoluble proteins. The supernatant protein concentration was measured spectrophotometrically at a 595-nm wave length. Sixty micrograms of total protein were fractionated by 4% to 20% gradient, SDS polyacrylamide gel electrophoresis (Invitrogen, San Diego, California), and transferred to PVDF membranes (Millipore, Bedford, Massachusetts). The membrane was incubated overnight at 4°C using specific antibodies as follows: anti-SDF-1 antibody diluted to 1:1000 (Leinco, San Diego, California) and anti-CXCR4 antibody diluted to 1:1000 (BD Biosciences, San Jose, California). Then, the membranes were incubated for 1 hour in the appropriate diluted secondary antibody (Jackson Immunolab, West Grove, Pennsylvania). Immune complexes were visualized with the enhanced chemiluminescence (ECL) detection system (Amersham, Piscataway, New Jersey). Specific protein densities were measured by densitometric quantification of autoradiograph films using NIH Image J 1.33 (National Institutes of Health, Bethesda, Maryland). Equal loading of various samples was confirmed by Ponceau S staining.
Immunohistochemistry
The atrial tissue taken from patients before and after CP/CPB (n = 6) was fixed in 10% formalin, embedded in paraffin, and sectioned (5 µm). Sections were deparaffinized in xylene, rehydrated in graded ethanol and phosphate-buffered saline solution (PBS), and permeabilized with citrate buffer. Endogenous peroxidase activity was eliminated by treatment with 1.5% hydrogen peroxide in PBS, followed by a PBS wash, and blocking overnight with 3% bovine serum albumin at room temperature. Incubation with anti–SDF-1 antibody diluted to 1:300 (Leinco) and anti-CXCR4 antibody diluted to 1:300 (BD Biosciences) was performed overnight at 4°C. The sections were then washed in PBS and incubated with biotin-conjugated secondary antibody anti-rabbit immunoglobulin G (Jackson Immunolab). Peroxidase was reversed by use of the diamino-benzidine-hydrogen method. The sections were then counterstained with methyl green, dehydrated, and mounted.
Coronary Microvessel Studies
Microvessels (50 to 150 µm internal diameters) were dissected from atrial tissue by use of a dissecting microscope (Olympus Optical, Tokyo, Japan) at original magnification of x10 to x60. Microvessels were placed in a microvessel chamber (University of Iowa Medical Instrumentation, Iowa City, Iowa), cannulated with dual glass micropipettes, and secured with 10-0 nylon monofilament suture (Ethicon, Somerville, New Jersey). Krebs buffer solution, warmed to 37°C and aerated with a 95% oxygen, 5% carbon dioxide mixture, was continuously circulated through the microvessel chamber. The microvesels were pressurized to 40 mm Hg in a no-flow state with a burette manometer filled with Krebs buffer solution. With an inverted microscope (at original magnification x40 to x200; Olympus Optical, Tokyo, Japan) connected to a video camera, the vessel image was projected onto a black-and-white television monitor. An electronic dimension analyzer (Living Systems Instrumentation, Burlington, Vermont) was used to measure internal lumen diameter, and measurements were recorded. Contraction responses were examined in coronary microvessels taken from atrial tissue before and after CP/CPB (n = 7). In addition, microvessels in atrial tissues both before and after CPB were pretreated with 5 µM of the CXCR4 antagonist, AMD3100 (n = 4), 1 µM of the p38 inhibitor SB203580 (n = 5), 0.5 µM of the ERK1/2 inhibitor U0126 (n = 7), or 0.05 µM of the JNK inhibitor ALX-159-600 (n = 6) for 30 minutes. Baseline diameter was defined as the diameter measured after equilibration in the buffer solution for 15 minutes. Diameters measured after treatment with SDF-1 were normalized to the baseline of diameter. The contraction responses of the microvessels to SDF-1 (10-8 to 1 ng/mL) were measured. Microvessels were washed with a Krebs buffer solution and allowed to equilibrate 15 to 30 minutes between interventions. Potassium chloride (100 mmol/L) was applied to test the viability and responsiveness of the vessel after completion of the above protocol.
Enzyme-Linked Immunosorbent Assay for SDF-1 in Human Plasma
Blood was obtained from the patients before CPB and after CPB (n = 7). Plasma was obtained after centrifugation. Quantitative immunoassays of SDF-1 were performed by SDF-1 enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, Minnesota) according to the maufacturer's instructions.
Data Analysis
All results are expressed as mean ± SEM. Microvessel responses are expressed as percentage contraction of the baseline diameter and were analyzed using two-way repeated measures analysis of variance. Western blots were analyzed after digitalization of x-ray films using a flat-bed scanner (ScanJet 4c; Hewlett Packard, Palo Alto, California) and NIH Image J 1.33 software (National Institutes of Health, Bethesda, Maryland). Comparisons between samples were analyzed by paired, two-tailed t test using GraphPad Prism 4 (GraphPad SoftWare, San Diego, California). All p values less than 0.05 were considered significant.
|
Results
|
|---|
The characteristics of the 23 patients who were enrolled in this study are shown in Table 1.
SDF-1 Protein Expression in Human Atrial Tissue and Plasma
To demonstrate differences in SDF-1 protein expression in human atrial tissue before and after CP/CPB, we carried out Western blot analysis (Fig 1A and B). The SDF-1 protein expression was significantly increased, 9.5 ± 3.5-fold, after CP/CPB compared with before CP/CPB (p = 0.03).
To determine the spatial distribution of the increased levels of SDF-1 protein after CP/CPB, we performed immunohistochemistry using anti–SDF-1 antibody (Fig 2). Staining of SDF-1 was observed in cardiomyocytes (Fig 2A and B), endothelial cells, and smooth muscle cells of coronary microvessels both before and after CP/CPB (Fig 2C and D). The intensity of SDF-1 after CP/CPB was qualitatively stronger than that before CP/CPB.
Plasma levels of SDF-1 were significantly increased after CP/CPB as compared with before (3.2 ± 2.8 versus 2.8 ± 1.7 ng /mL, respectively; p = 0.03).
CXCR4 Protein Expression Before and After CP/CPB
Because SDF-1 binds only to CXCR4, we compared CXCR4 expression in human atrial tissue before and after CP/CPB by Western blot analysis (Fig 3A and B) and also confirmed localization of CXCR4 by immunohistochemical analysis (Fig 3C). Western blot analysis showed no significant differences of CXCR4 levels between before and after CP/CPB (p = 0.58). Positive staining of CXCR4 was found only in coronary endothelial cells, and not in smooth muscle cells or cardiomyocytes.
View larger version (39K):
[in this window]
[in a new window]
|
Fig 3. (A, B) Western blot analysis of CXCR4 in human atrial tissue from patients undergoing coronary artery bypass graft survery before and after cardioplegia and cardiopulmonary bypass (CP/CPB [n = 6]). Protein levels of CXCR4 in human atrial tissue samples were unchanged between before and after CP/CPB. Results are expressed as mean ± SEM. (C) Representative immunohistochemical sections of human atrial sections stained by anti-CXCR4 antibody. Staining of CXCR4 was found in endothelial cells (arrow) of the before and after CP/CPB sections, but not in smooth muscle cells.
|
|
Coronary Microvessel Functional Studies
To study the functional effects of SDF-1/CXCR4 on the coronary endothelium and to determine the role of MAPK pathways in SDF-1 signaling, we performed coronary microvessel studies (Figs 4 and 5).
Samples for microvessel studies were taken from 16 patients undergoing cardiac surgery. No significant difference in internal diameter was observed between the groups before and after CP/CPB at baseline (99.9 ± 9.5 versus 93.9 ± 6.4 µm, p = 0.62). As shown in Figure 4A, SDF-1 induced coronary microvessel contraction before and after surgery. The coronary microvessel contraction induced by SDF-1 was significantly increased after exposure to CP/CPB (p = 0.046). As shown in Figure 4B, the coronary microvessel contraction induced by SDF-1 after CP/CPB was blocked by a specific CXCR4 antagonist, AMD3100 (p = 0.047).
To study signaling pathways involved in the coronary microvessel contraction induced by SDF-1, we pretreated vessels with three different inhibitors of MAPK, including SB203580 (p38 MAPK inhibitor, 1µM), UO126 (ERK1/2 inhibitor, 0.5µM), and ALX-159-600 (JNK inhibitor, 0.05µM), followed by administration of SDF-1. The SDF-1–induced microvessel contraction was inhibited by SB203580 (p = 0.049), UO126 (p = 0.046), and ALX-159-600 (p = 0.06) as shown in Figure 5. Thus, inhibitors of p38 MAPK, ERK1/2, and JNK signaling pathways blocked coronary microvessel contraction caused by SDF-1. No significant difference in the percent contraction after treatment with 100 mM of potassium chloride at the completion of the protocols was observed between the groups before and after CP/CPB (20.3% ± 8.6% versus 19.5% ± 5.3%, p = 0.98). Microvessel contraction was unaffected by DMSO, which was used to dissolve the reagents, at the concentrations used.
|
Comment
|
|---|
Stromal-derived factor-1 is an important chemokine involved in cell homing and trafficking in response to injury. The results of the present study demonstrate that CP/CPB induces the expression of SDF-1 as well as activation of downstream signaling pathways involved in SDF-1/CXCR4 signaling, which, in turn, have functional effects on the coronary microvasculature. This conclusion is based on the following results: (1) Myocardial protein expression of SDF-1 is increased after CP/CPB, whereas CXCR4 protein expression remains unchanged. This increased expression is clearly observed in cardiomyocytes, endothelial cells, and smooth muscle cells after CP/CPB. (2) Coronary microvessel contraction in response to SDF-1 is significantly increased after CP/CPB, and blocked by CXCR4 antagonist, AMD3100. (3) The coronary microvessel contraction induced by SDF-1 after CP/CPB is inhibited by U0126 (ERK1/2 inhibitor) and SB203580 (p38 MAPK inhibitor), and JNK inhibitor.
Stromal-derived factor-1 expression is increased after ischemia in various animal models including acute myocardial infarction [4, 14], hind-limb ischemia [9], and skin flap [5]. Although it is generally accepted that cardiac tissue is subjected to controlled ischemia-reperfusion injury after CP/CPB, the tissue injury caused by CP/CPB is different from pure ischemic injury reported in many animal models. Our study demonstrates that CP/CPB increase SDF-1 expression early after CP/CPB. Stromal-derived factor-1 is constitutively expressed and secreted by several tissues and organs including endothelial cells and muscle tissue in response to injury [9]. De Falco and colleagues [9] showed increased SDF-1 expression in arterioles as well as muscle fibers after hind-limb ischemia. In agreement with their results, we also found increased SDF-1 expression in endothelial and smooth muscle cells as well as cardiomyocytes after CP/CPB. Thus, cardiomyocytes, endothelial cells, and smooth muscle cells are all likely to be involved in the production of SDF-1.
Whether plasma levels of SDF-1 are altered in response to ischemia remains controversial. Serum levels of SDF-1 have been shown to decrease [4, 15] or remain unchanged [16] after onset of acute myocardial infarction. Mechanisms by which plasma levels of SDF-1 are decreased in peripheral blood are still not clear. On the other hand, other groups have reported increased plasma levels of SDF-1 shortly after hind limb ischemia [9]. Our results indicate that after CP/CPB, in addition to a 9.5-fold increased expression in the ischemic myocardial tissue, plasma levels of SDF-1 are also increased by about 15%. Plasma levels of SDF-1 may also be affected by the type of tissue damaged and the nature of the ischemic insult.
Functional CXCR4 expression on endothelial cells is regulated by various cytokines and growth factors. In-vitro experiments using endothelial cells have demonstrated that vascular endothelial growth factor, basic fibroblast growth factor [17], and hypoxia inducible factor-1 [18] mediate up-regulation of CXCR4, whereas interferon-
[19], interleukin-1, and tumor necrosis factor- [20] induce down-regulation of CXCR4. Expression of CXCR4 in atrial tissue was unchanged between before versus after CP/CPB specimens in this study. It is well established that CP/CPB result in changes in plasma levels of cytokines and growth factors such as vascular endothelial growth factor [21], interferon-gamma [22], interleukin-1, and tumor necrosis factor- [23]. The altered levels of cytokines and growth factors induced by CP/CPB may affect the function of CXCR4, even though the expression remains unchanged. It is also possible that changes in receptor expression occur in the hours to days after CP/CPB and, therefore, were not captured in our study.
To evaluate the functional endothelial response induced by SDF-1, we evaluated changes in coronary microvessel reactivity. We found that SDF-1 induced coronary microvessel contraction, and that this contraction was significantly increased after CP/CPB. Furthermore, the coronary microvessel contraction was blocked by the specific CXCR4 antagonist, suggesting that the microvessel contraction was induced by the SDF-1/CXCR4 signaling pathways. Microvascular contraction in response to potassium chloride was unchanged before and after CP/CPB in this study. In addition, we have previously shown that the coronary microvessel contraction induced by thromboxane A2 analog (U46619), an endothelium-independent vasoconstrictor, was unchanged before and after CP/CPB [24]. These lines of evidence suggest that the coronary microvessel contraction in this study was induced by SDF-1/CXCR4 interactions, and was not due to endothelial dysfunction or to a nonspecific change in vascular smooth muscle function.
In addition, we found that MAPKs signaling pathways are involved in the coronary microvessel contraction induced by SDF-1 after CP/CPB. Talmor and associates [1] demonstrated that the phosphorylated protein expression associated with p38, ERK1/2, and JNK increased after CP/CPB. In this study, we showed that the coronary microvessel contraction induced by SDF-1 after CP/CPB was significantly blocked by p38 MAPK inhibitor and ERK1/2 inhibitor, and moderately inhibited by JNK inhibitor. Interestingly, Bendall and colleagues [25] have demonstrated that defective p38 MAPK signaling impairs chemotactic response to SDF-1 independent of ERK and PI3 kinase pathways, suggesting that p38 MAPK is involved in the SDF-1–mediated signaling pathway. We have previously shown that activation of p38 MAPK is increased after CP/CPB in endothelial cells [26]. Although the effect of the JNK inhibitor was not statistically significant, it is likely that JNK is also involved in the mechanism. These observations suggest that the p38 MAPK signaling pathway is an important mediator of SDF-1/CXCR4 signaling after CP/CPB.
It is well known that the SDF-1/CXCR4 interaction is essential for trafficking and migration of mononuclear cells, and likely represents a tissue repair mechanism. Our present results suggest that the increased expression of SDF-1 and the coronary microvascular contraction induced by SDF-1 may contribute to mononuclear cell trafficking as a first step of a tissue repair mechanism and may lead to angiogenesis or vascular remodeling in the myocardium during cardiac surgery.
Although we have demonstrated functional effects of SDF-1/CXCR4 interactions on the coronary endothelium in this study, there are certain limitations to this study. Our experiments were performed using atrial myocardial tissue because of the unavailability of ventricular tissue from patients. In the clinical setting, ventricular myocardium is the tissue of interest for therapeutic angiogenesis, and while there are many similarities, important differences may exist between the two. In addition, because the number of tissue samples in each group was limited, we could not evaluate the effects of various comorbidities, namely, diabetes mellitus, hypercholesterolemia, and so forth, on the protein expression and microvessel response. Further studies will be required to address these issues.
In conclusion, we have demonstrated that short duration of controlled ischemia-reperfusion injury in patients undergoing CP/CPB leads to increased myocardial and plasma expression of SDF-1 and that SDF-1 induces coronary microvascular contraction through activation of MAPK.
|
Acknowledgments
|
|---|
This work was supported by National Institutes of Health Grants R01 HL46716 (FWS) and R01 HL69024 (FWS).
|
References
|
|---|
- Talmor D, Applebaum A, Rudich A, Shapira Y, Tirosh A. Activation of mitogen-activated protein kinases in human heart during cardiopulmonary bypass Circ Res 2000;86:1004-1007.[Abstract/Free Full Text]
- Khan TA, Bianchi C, Ruel M, Voisine P, Sellke FW. Mitogen-activated protein kinase pathways and cardiac surgery J Thorac Cardiovasc Surg 2004;127:806-811.[Abstract/Free Full Text]
- Voisine P, Ruel M, Khan TA, et al. Differences in gene expression profiles of diabetic and nondiabetic patients undergoing cardiopulmonary bypass and cardioplegic arrest Circulation 2004;110(Suppl II):280-286.
- Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury Circulation 2004;110:3300-3305.[Abstract/Free Full Text]
- Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 Nat Med 2004;10:858-864.[Medline]
- Horuk R. Chemokine receptors Cytokine Growth Factor Rev 2001;12:313-335.[Medline]
- Ganju RK, Brubaker SA, Meyer J, et al. The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways J Biol Chem 1998;273:23169-23175.[Abstract/Free Full Text]
- Oh SB, Endoh T, Simen AA, Ren D, Miller RJ. Regulation of calcium currents by chemokines and their receptors J Neuroimmunol 2002;123:66-75.[Medline]
- De Falco E, Porcelli D, Torella AR, et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells Blood 2004;104:3472-3482.[Abstract/Free Full Text]
- Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarctionfinal one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 2004;44:1690-1699.[Abstract/Free Full Text]
- Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation Lancet 2003;361:47-49.[Medline]
- Hamano K, Nishida M, Hirata K, et al. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart diseaseclinical trial and preliminary results. Jpn Circ J 2001;65:845-847.[Medline]
- Urbich C, Dimmeler S. Endothelial progenitor cells functional characterization Trends Cardiovasc Med 2004;14:318-322.[Medline]
- Ma J, Ge J, Zhang S, et al. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction Basic Res Cardiol 2005.
- Wojakowski W, Tendera M, Michalowska A, et al. Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction Circulation 2004;110:3213-3220.[Abstract/Free Full Text]
- Leone AM, Rutella S, Bonanno G, et al. Endogenous G-CSF and CD34(+) cell mobilization after acute myocardial infarction Int J Cardiol 2006(in press).
- Salcedo R, Wasserman K, Young HA, et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cellsin vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 1999;154:1125-1135.[Abstract/Free Full Text]
- Schioppa T, Uranchimeg B, Saccani A, et al. Regulation of the chemokine receptor CXCR4 by hypoxia J Exp Med 2003;198:1391-1402.[Abstract/Free Full Text]
- De Bleecker JL, Meire VI, Declercq W, Van Aken EH. Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies Neuromuscul Disord 1999;9:239-246.[Medline]
- Gupta SK, Lysko PG, Pillarisetti K, Ohlstein E, Stadel JM. Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines J Biol Chem 1998;273:4282-4287.[Abstract/Free Full Text]
- Cotton JM, Mathur A, Hong Y, Brown AS, Martin JF, Erusalimsky JD. Acute rise of circulating vascular endothelial growth factor-A in patients with coronary artery disease following cardiothoracic surgery Eur Heart J 2002;23:953-959.[Abstract/Free Full Text]
- Sharma M, Ganguly NK, Chaturvedi G, Thingnam SK, Majumdar S, Suri RK. Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery Mol Cell Biochem 2003;247:23-30.[Medline]
- Gormley SM, McBride WT, Armstrong MA, et al. Plasma and urinary cytokine homeostasis and renal function during cardiac surgery without cardiopulmonary bypass Cytokine 2002;17:61-65.[Medline]
- Metais C, Li J, Simons M, Sellke FW. Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusionrole of COX-2 expression. Circulation 1999;100(Suppl II):328-334.
- Bendall LJ, Baraz R, Juarez J, Shen W, Bradstock KF. Defective p38 mitogen-activated protein kinase signaling impairs chemotaxic but not proliferative responses to stromal-derived factor-1alpha in acute lymphoblastic leukemia Cancer Res 2005;65:3290-3298.[Abstract/Free Full Text]
- Khan TA, Bianchi C, Araujo EG, Ruel M, Voisine P, Sellke FW. Activation of pulmonary mitogen-activated protein kinases during cardiopulmonary bypass J Surg Res 2003;115:56-62.[Medline]
This article has been cited by other articles:
|
|
|
|
 
O. Dotsenko and M. Jahangiri
Endogenous stem cells in patients undergoing coronary artery bypass graft surgery
Eur. J. Cardiothorac. Surg.,
September 1, 2009;
36(3):
563 - 571.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
