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1.
J Hematol Oncol ; 2: 7, 2009 Feb 07.
Article in English | MEDLINE | ID: mdl-19200397

ABSTRACT

BACKGROUND: Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli. Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization. Previous studies have shown that manipulating Egr-1 expression can have either positive or negative effects on tumor growth. We hypothesized that Egr-1 knockout mice might exhibit reduced tumor growth, possibly due to a reduced capacity to respond to angiogenic signals from a growing tumor. RESULTS: We injected 106 Lewis lung carcinoma (LLC1) cells subcutaneously in the flank of wild type and Egr-1 knockout mice. The average mass of tumors from wild type mice at 12 days after implantation was 413 +/- 128 mg, while those from Egr-1-/- mice was 219 +/- 81 mg (p = 0.001, mean +/- SD). However, sectioning the tumors and staining with anti-CD31 antibodies revealed no difference in the vascularity of the tumors and there was no difference in angiogenic growth factor expression. Expression of the chemokine Mig (CXCL9) was increased 2.8-fold in tumors from knockout mice, but no increase was found in serum levels of Mig. Natural killer cells have a 1.7-fold greater prevalence in the CD45+ cells found in tumors from Egr-1-/- mice compared to those from wild type mice. Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages. CONCLUSION: Mice deficient in Egr-1 exhibit reduced growth of LLC1 tumors, and this phenomenon is associated with overexpression of Mig locally within the tumor. There are no obvious differences in tumor vascularity in the knockout mice. Natural killer cells accumulate in the tumors grown in Egr-1-/- mice, providing a potential mechanism for the reduction in growth.


Subject(s)
Chemokine CXCL9/genetics , Early Growth Response Protein 1/genetics , Neoplasms/genetics , Neoplasms/pathology , Tumor Burden/genetics , Animals , Carcinoma, Lewis Lung/genetics , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Cell Line, Tumor , Cell Proliferation , Cells, Cultured , Chemokine CXCL9/metabolism , Gene Expression Regulation, Neoplastic , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Leukemic Infiltration/genetics , Leukemic Infiltration/pathology , Macrophages/metabolism , Macrophages/pathology , Melanoma, Experimental/genetics , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/metabolism
2.
J Thorac Cardiovasc Surg ; 133(2): 478-484.e2, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17258586

ABSTRACT

OBJECTIVE: Improvements in ventricular function after cellular cardiomyoplasty appear to be limited by the poor survival of the cellular implants. Angiogenic pretreatment of infarcted myocardium may improve implanted cell survival and consequently myocardial function. METHODS: Fischer 344 rats underwent coronary artery ligation and injection of an adenovirus encoding vascular endothelial growth factor 121 or of saline solution at increasing intervals after ligation. Myocardial perfusion and mass preservation were assessed. On the basis of these data, four groups of animals underwent coronary ligation and adenovirus with or without syngeneic skeletal myoblast administration: (1) adenovirus at ligation and myoblasts 3 weeks later (n = 7), (2) saline solution at ligation and myoblasts 3 weeks later (n = 8), (3) saline solution at ligation and 3 weeks later (n = 8), and (4) saline solution at ligation and adenovirus with myoblasts 3 weeks later (n = 5). Left ventricular ejection fraction was analyzed by echocardiography before coronary ligation and 3 and 5 weeks later, after which cell survival was assessed in harvested tissues. RESULTS: Myocardial infarct perfusion was at least 50% greater in animals treated with adenoviral vector than with saline solution immediately after ligation (P < .02). In comparison, delayed adenovirus administration did not significantly diminish infarct perfusion but resulted in decreased myocardial preservation (P < .05). Accordingly, adenovirus administration nearly tripled implanted myoblast survival relative to saline solution-treated animals (P = .004). Left ventricular ejection fraction was improved, however, only after cell implantation with adenovirus pretreatment (P = .027). CONCLUSION: Angiogenic strategies can help to preserve myocardium jeopardized by acute coronary occlusions. Angiogenic pretreatment enhances the efficacy of cellular cardiomyoplasty.


Subject(s)
Angiogenic Proteins/pharmacology , Cardiomyoplasty/methods , Myoblasts, Skeletal/transplantation , Myocardial Infarction/surgery , Ventricular Dysfunction, Left/pathology , Adenoviridae , Analysis of Variance , Animals , Biopsy, Needle , Cell Survival , Disease Models, Animal , Echocardiography , Male , Myocardial Contraction/physiology , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/mortality , Myocardial Infarction/pathology , Photomicrography , Probability , Rats , Rats, Inbred F344 , Reference Values , Survival Rate , Treatment Outcome , Vascular Endothelial Growth Factor A/pharmacology , Ventricular Dysfunction, Left/physiopathology , Ventricular Remodeling/physiology
3.
J Thorac Cardiovasc Surg ; 131(1): 138-45, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16399305

ABSTRACT

BACKGROUND: Arteriogenesis has been implicated as an important biologic response to acute vascular occlusion. The early growth response 1 (Egr-1) gene encodes an immediate-early response transcription factor that is upregulated by changes in vascular strain and that in turn upregulates a number of putative angiogenic and arteriogenic growth factors. We therefore hypothesized that early growth response 1 might be a critical arteriogenic messenger that induces revascularization in the setting of acute vascular occlusions. METHODS: Wild-type or Egr-1-/- (null) C57 BL mice, or Sprague-Dawley rats, underwent unilateral iliofemoral artery excision and subsequent analyses for angiogenesis and arteriogenesis through cell-specific immunohistochemistry. Rats were also administered an adenoviral vector encoding for Egr-1 (AdEgr group), noncoding vectors (AdNull group), or saline, after which these animals were assessed by means of serial laser Doppler perfusion imaging and morphologic examination of rat foot-pad ischemic lesions. RESULTS: Egr-1 wild-type mice demonstrated an equivalent number of capillaries but a greater number of arterioles following excision versus Egr-1 null mice. AdEgr group rats demonstrated greater distal perfusion from 7 to 21 days after excision compared with control animals (P < .02), which approximated normal perfusion at 21 days after excision. AdEgr group rats also demonstrated greater arteriolar density and less severe ischemic foot-pad lesions than control animals. CONCLUSION: These data suggest the importance of Egr-1 as a critical and potentially therapeutic mediator of revascularization after vascular occlusion and implicate arteriogenesis (collateral vessel formation) as a critical component of this process.


Subject(s)
Arteries/physiology , Early Growth Response Protein 1/physiology , Neovascularization, Physiologic/physiology , Animals , Arterial Occlusive Diseases/therapy , Early Growth Response Protein 1/genetics , Genetic Therapy , Male , Mice , Mice, Inbred C57BL , Neovascularization, Physiologic/genetics , Rats , Rats, Sprague-Dawley
5.
J Thorac Cardiovasc Surg ; 128(4): 595-601, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15457161

ABSTRACT

BACKGROUND: The early growth response 1 gene (Egr1) encodes for an immediate to early response transcription factor that is upregulated by changes in vascular strain and hypoxia and in turn upregulates the downstream expressions of a number of angiogenic growth factors. We therefore hypothesized that early growth response 1 may be a critical early messenger governing revascularization in the setting of acute vascular occlusions. METHODS: C57 BL/6 mice deficient in the Egr1 gene (knockout) and their wild-type litter mates underwent ligation and excision of the femoral artery with or without the previous administration of 2.7 x 10(9) particle units of an adenoviral vector coding for the vascular endothelial growth factor gene (VEGF) or Egr1. Distal hind limb perfusion was serially measured in these animals with laser Doppler perfusion imaging. RESULTS: Wild-type mice (n = 9) had nearly complete restitution of hind limb perfusion by day 35 after ligation. In contrast, all noninjected Egr1 knockout mice (n = 5) had severe ipsilateral limb necrosis develop between 1 and 4 days after ligation (P <.0001). Egr1 knockout mice injected with VEGF vector (n = 4) demonstrated significantly improved perfusion relative to baseline by postligation day 28, which persisted to postligation day 35 (P <.05). Egr1 knockout animals injected with Egr1 vector (n = 7) demonstrated a partial recovery of hind limb perfusion relative to VEGF vector-treated knockout animals at postligation day 4 (P <.01), which persisted to day 35. CONCLUSIONS: These findings suggest that early growth response 1 plays a pivotal role in reperfusion responses to vascular occlusion in mice and possibly other mammals.


Subject(s)
DNA-Binding Proteins/genetics , Femoral Artery/surgery , Immediate-Early Proteins/genetics , Ischemia/etiology , Transcription Factors/genetics , Adenoviridae , Animals , Blotting, Northern , DNA-Binding Proteins/physiology , Early Growth Response Protein 1 , Gene Deletion , Genetic Vectors , Hindlimb/blood supply , Homeostasis/physiology , Homozygote , Immediate-Early Proteins/physiology , Ligation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Rats, Sprague-Dawley , Transcription Factors/physiology , Vascular Endothelial Growth Factor A/genetics , Zinc Fingers
6.
J Thorac Cardiovasc Surg ; 127(4): 1041-9; discussion 1049-51, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15052201

ABSTRACT

BACKGROUND: Cell implantation into areas of myocardial infarction (cellular cardiomyoplasty) may be limited in efficacy because of the lack of blood supply to these areas of myocardium, resulting in early loss of transplanted cells. We therefore tested the hypothesis that pretreatment of infarcted myocardium with angiogenic therapy, followed by cell transplant, would be more effective than the application of either strategy alone. METHODS: Fischer 344 rats underwent left coronary artery ligation and injection of an adenovirus encoding VEGF 121, an empty expression cassette control vector, or saline solution. Capillary density in the infarcted region was determined in preliminary studies. Cardiomyocytes harvested from syngeneic Fischer rat fetuses were prelabeled and then injected directly into the infarct area 3 weeks after vector administration. Exercise treadmill testing was performed 2 weeks after cell transplantation, after which a cell viability index was calculated as the number of implanted (prelabeled) nuclei divided by the number of coadministered microspheres detected in sections of implanted myocardium. RESULTS: Capillary density in the area of infarction was significantly greater in adenovirus encoding VEGF 121 compared with rats injected with saline solution (P =.001). The cell survival index was also greater in adenovirus encoding VEGF 121 compared with animals injected with empty expression cassette control or saline solution (P =.0045). Exercise tolerance was nearly doubled in animals receiving adenovirus encoding VEGF 121 3 weeks prior to cell implantation compared with animals receiving adenovirus encoding VEGF 121 or cells alone or those receiving adenovirus encoding VEGF 121 at the time of cell implantation (P <.001). CONCLUSIONS: Pretreatment of an infarcted region of the heart with angiogenic mediators such as VEGF can enhance the efficacy of cellular cardiomyoplasty, presumably by creating a more favorable environment for the survival of transplanted cells.


Subject(s)
Cardiomyoplasty , Cell Transplantation , Fetal Heart/cytology , Myocytes, Cardiac/transplantation , Animals , Cell Survival/drug effects , Cell Survival/physiology , Combined Modality Therapy , Disease Models, Animal , Exercise Tolerance/drug effects , Exercise Tolerance/physiology , Male , Models, Cardiovascular , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Myocardial Infarction/physiopathology , Myocardial Infarction/therapy , Myocardium/cytology , Myocardium/ultrastructure , Myocytes, Cardiac/ultrastructure , Rats , Rats, Inbred F344 , Treatment Outcome , Vascular Endothelial Growth Factor A/pharmacology
7.
J Thorac Cardiovasc Surg ; 127(2): 535-40, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14762365

ABSTRACT

BACKGROUND: Angiogenic gene therapy has been demonstrated to enhance perfusion to ischemic tissues, but it is unknown whether the administration of angiogenic growth factors will increase blood flow to nonischemic tissues. This study investigates whether enhanced myocardial perfusion can be mediated by adenovirus-mediated transfer of vascular endothelial growth factor 121 cDNA to nonischemic myocardium. METHODS: New Zealand White rabbits received adenovirus (5 x 10(10) particle units) encoding for vascular endothelial growth factor 121 (n = 14) or a control vector without a transgene (n = 13) or saline solution (n = 9) via direct myocardial injection. Fluorescent microsphere perfusion studies and histologic analyses were performed 4 weeks later. In a parallel study, exercise treadmill testing was performed to assess the functional effects of this therapy in Sprague-Dawley rats. RESULTS: Microsphere assessment of myocardial perfusion in rabbits 4 weeks after adenovirus-encoding vascular endothelial growth factor administration was greater than that for rats injected with control vector without a transgene or saline solution (3.2 +/- 0.5 vs 2.7 +/- 0.7 and 2.4 +/- 0.4, respectively; P <.03). The endothelial cell count per high power field was increased in animals injected with adenovirus-encoding vascular endothelial growth factor versus animals injected with control vector without a transgene or saline solution (147 +/- 27 vs 123 +/- 14 and 125 +/- 16 cells, respectively), although this did not reach statistical significance (P =.12). Rats treated with adenovirus-encoding vascular endothelial growth factor also demonstrated prolonged exercise tolerance compared with rats injected with control vector without a transgene or saline solution (exhaustion time: 26 +/- 5 minutes vs 19 +/- 2 minutes and 20 +/- 3 minutes, respectively; P =.006). CONCLUSIONS: Adenovirus encoding-mediated transfer of vascular endothelial growth factor 121 induces an enhancement in regional perfusion in nonischemic myocardium that corresponds to changes in exercise tolerance. Adenovirus-encoding vascular endothelial growth factor therapy may be useful for inducing angiogenesis in the nonischemic state, such as for prophylactic therapy of early coronary artery disease.


Subject(s)
Adenoviridae/genetics , DNA, Complementary/genetics , Exercise Tolerance/drug effects , Exercise Tolerance/genetics , Gene Transfer Techniques , Genetic Therapy , Myocardial Ischemia/genetics , Myocardial Ischemia/therapy , Myocardial Reperfusion , Vascular Endothelial Growth Factor A/genetics , Animals , Coronary Circulation/drug effects , Endothelial Cells/drug effects , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Genetic Vectors/genetics , Heart Septum/drug effects , Heart Ventricles/drug effects , Male , Models, Animal , Models, Cardiovascular , Rabbits , Rats , Rats, Sprague-Dawley , Time Factors , Vascular Endothelial Growth Factor A/administration & dosage
8.
J Thorac Cardiovasc Surg ; 123(6): 1101-13, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12063456

ABSTRACT

BACKGROUND: Myocardial ischemia is the most common cause of congestive heart failure. Angiogenic therapy has recently been demonstrated to enhance myocardial perfusion in the ischemic setting. We therefore hypothesized that administration of adenovirus encoding for vascular endothelial growth factor could be used to enhance myocardial function in a pacing-induced model of heart failure. METHODS: Yorkshire swine underwent a left thoracotomy with placement of a ventricular epicardial pacing system. Animals received adenovirus coding either for the 121-amino-acid isoform of vascular endothelial growth factor (Ad(CU)VEGF121.1 group, n = 8) or a null vector coding for no genes (AdNull group, n = 8). The adenovirus was administered in the left ventricular free wall as 10 transepicardial injections of 100 microL each (total dose of 10(11) particle units). After a 1-week recovery period, animals were paced at a rate of 230 beats/min for 7 days to induce heart failure. Transthoracic echocardiographic and sonomicrometric measurements were performed before pacing (baseline), on termination of pacing (day 0), and then weekly for 3 weeks. RESULTS: The fractional area change was significantly decreased in AdNull animals at day 0 after pacing compared with the Ad(CU)VEGF121.1 animals (29% +/- 14% vs 46% +/- 8%, P =.02). The fractional area change recovered to baseline values within 7 days in the Ad(CU)VEGF121.1 animals (62% +/- 7%) but remained significantly impaired in the AdNull group compared with that in the Ad(CU)VEGF121.1 animals up to day 21 (P =.04). Similarly, fractional wall thickening demonstrated a decrease at day 0 after pacing that was greater (P <.05) in the AdNull group compared with that in the Ad(CU)VEGF121.1 group in 5 of 6 segments. Fractional wall thickening returned to levels approximating prepacing values in all segments within 7 days in the Ad(CU)VEGF121.1 group but remained significantly impaired compared with prepacing fractional wall thickening (P <.05) in the AdNull group in 5 of 6 segments up to day 21 after pacing. Segmental shortening, as measured by sonomicrometry, also was significantly decreased at day 7 in the AdNull group compared with that in the Ad(CU)VEGF121.1 group (10% +/- 4% vs 16% +/- 3%, P =.004) and remained significantly impaired (P <.05) in the AdNull group at day 14 and 21 when compared with baseline values. CONCLUSION: Preservation of cardiac performance and a more rapid recovery of myocardial function can be achieved in a model of pacing-induced cardiomyopathy with adenovirus-mediated administration of vascular endothelial growth factor compared with that seen in a null virus control group. These data suggest that angiogenic therapy may be useful clinically in treating cardiomyopathy.


Subject(s)
Endothelial Growth Factors/genetics , Genetic Therapy , Heart Failure/therapy , Lymphokines/genetics , Adenoviridae/genetics , Animals , Cardiac Pacing, Artificial , Disease Models, Animal , Gene Transfer Techniques , Heart Failure/genetics , Image Processing, Computer-Assisted , Male , Protein Isoforms , Swine , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
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