Search PubMed⌕ Search

Biomedical subjects

Denis Angoulvant

Publications and source records attributed to Denis Angoulvant.

10 recordsLinked to original sources
PubMed2006

c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes.

Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2), a key proinflammatory mediator. The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE(2) biosynthesis. In neonatal cardiomyocytes, interleukin-1beta and lipopolysaccharide (LPS) both stimulated mPGES-1 mRNA expression and increased mPGES-1 mRNA stability and protein synthesis but failed to increase mPGES-1 mRNA transcription. Treatment with the JNK1/2 inhibitor, SP600125, abrogated the increases in mPGES-1 mRNA stability, mPGES-1 protein synthesis, and PGE(2) release induced by interleukin-1beta or LPS. mPGES-1 protein synthesis was observed in LPS-stimulated neonatal cardiomyocytes from jnk1(-/-) or jnk2(-/-) mice. In contrast, infection of jnk1(-/-) cardiomyocytes with an adenovirus encoding phosphorylation-resistant JNK2 (ad-JNK2-DN), or of jnk2(-/-) cardiomyocytes with ad-JNK1-DN, significantly decreased LPS-stimulated mPGES-1 protein synthesis. Similarly, co-infection with ad-JNK1-DN and ad-JNK2-DN attenuated LPS-stimulated mPGES-1 protein synthesis in cardiomyocytes from wild type mice. Targeted deletion of the gene encoding mPGES-1 led to a 3.2-fold decrease in LPS-stimulated PGE(2) release by cardiomyocytes in comparison with wild type cells but had no effect on COX-1, COX-2, mPGES-2, or cytosolic PGES mRNA levels. These studies provide direct evidence that mPGES-1 mRNA levels in cardiomyocytes are augmented by stabilization of mPGES-1 mRNA, that JNK1 or JNK2 can participate in the regulation of mPGES-1 protein synthesis in these cells, and that mPGES-1 catalyzes the majority of LPS-induced PGE(2) biosynthesis by cardiomyocytes.

Animals↗
PubMed2006

Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines.

Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit+ cells in the heart. These cells were traced back to a bone marrow origin, using genetic tagging in bone marrow chimeric mice. The recruited c-kit+ cells established a proangiogenic milieu in the infarct border zone by increasing VEGF and by reversing the cardiac ratio of angiopoietin-1 to angiopoietin-2. These oscillations potentiated endothelial mitogenesis and were associated with the establishment of an extensive myofibroblast-rich repair tissue. Mutations in the c-kit receptor interfered with the mobilization of the cells to the heart, prevented angiogenesis, diminished myofibroblast-rich repair tissue formation, and led to precipitous cardiac failure and death. Replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype. We conclude that, consistent with their documented role in tumorigenesis, bone marrow c-kit+ cells act as key regulators of the angiogenic switch in infarcted myocardium, thereby driving efficient cardiac repair.

Animals↗
PubMed2005

Cell transplantation preserves cardiac function after infarction by infarct stabilization: augmentation by stem cell factor.

OBJECTIVE: We hypothesized that implantation of adult mesenchymal stem cells after acute myocardial infarction mobilizes bone marrow precursor cells by activating the stem cell factor pathway, and that overdriving this pathway would enhance the beneficial effects of cell transplantation. METHODS: After coronary ligation, medium, mesenchymal stem cells, or stem cell factor-overproducing mesenchymal stem cells were injected into the anterior left ventricle. Cells from beta-galactosidase transgenic mice enabled tracking of injected cells. The global and local impact of the cells was evaluated by measuring cytokine levels, endothelial progenitor cells, and myocardial angiogenesis, and by addressing cardiomyogenesis with confocal microscopy. The impact on cardiac function was evaluated by pressure-volume loops. Ventricular morphometrics were measured after in situ perfusion-fixation of the hearts at physiologic pressures. RESULTS: Implantation of mesenchymal stem cells increased myocardial stem cell factor levels 2.0-fold, endothelial progenitor cell mobilization 2.7-fold, and myocardial angiogenesis 2.3-fold (P < .05), but did not induce mitogenesis in host cardiomyocytes or give rise to beta-galactosidase-expressing cardiomyocytes. Cell-transplanted groups had improved indices of cardiac function, including preload recruitable stroke work and end-systolic elastance (P < .001). Cell transplantation resulted in 2.0-fold smaller ventricular volumes (P = .001) and 2.0-fold reduced infarct scar area (P = .056), but had no effect on the volume of spared myocardium. Stem cell factor overproduction imparted greater functional benefit without inducing detectable histologic cardiomyocyte regeneration. CONCLUSION: Mesenchymal stem cell implantation after myocardial infarction facilitates functional cardiac regeneration without myocyte regeneration through augmentation of endogenous infarct repair, which is enhanced by stem cell factor.

Animals↗
PubMed2005

Cell transplantation improves ventricular function after a myocardial infarction: a preclinical study of human unrestricted somatic stem cells in a porcine model.

BACKGROUND: Cell transplantation offers the promise in the restoration of ventricular function after an extensive myocardial infarction, but the optimal cell type remains controversial. Human unrestricted somatic stem cells (USSCs) isolated from umbilical cord blood have great potential to differentiate into myogenic cells and induce angiogenesis. The present study evaluated the effect of USSCs on myocardial regeneration and improvement of heart function after myocardial infarction in a porcine model. METHOD AND RESULTS: The distal left anterior descending artery of Yorkshire pigs (30 to 35 kg) was occluded by endovascular implantation of a coil. Four weeks after infarction, single-photon emission computed tomography technetium 99m sestamibi scans (MIBI) and echocardiography were performed. USSCs (100 x 10(6)) or culture media were then directly injected into the infarcted region (n=8 per group). Pigs were immunosuppressed by daily administration of cyclosporin A. At 4 weeks after transplantation, MIBI and echocardiography were repeated and heart function was also assessed with a pressure-volume catheter. The infarcted myocardium and implanted cells were studied histologically. MIBI showed improved regional perfusion (P<0.05) and wall motion (P<0.05) of the infarct region in the transplant group compared with the control. Ejection fraction evaluated by both MIBI and echocardiography decreased in the control group but increased in the transplant group (P<0.01). Scar thickness of the transplant group was higher than the control. The grafted cells were detected 4 weeks after transplantation by both immunohistochemistry and in situ hybridization. CONCLUSIONS: Engrafted USSCs were detected in the infarct region 4 weeks after cell transplantation, and the implanted cells improved regional and global function of the porcine heart after a myocardial infarction. This study suggests that the USSC implantation will be efficacious for cellular cardiomyoplasty.

Animals↗
PubMed2005

Cardiac restoration: frontier or fantasy?

Heart failure is reaching epidemic proportions in Canada. The current medical and surgical therapies are inadequate to restore cardiac function. Increasingly, cell therapy has been investigated as a novel approach to regenerate the heart and to restore function. Animal studies have been promising and clinical trials are proceeding. Early results suggest that cell therapy may be efficacious in humans as well, but adverse events have been noted. Although the optimal cell type, mode of delivery and ideal patient population have not been identified, the bulk of the evidence suggests that both cardiologists and cardiac surgeons will use cellular therapy to treat heart failure in the future.

Animals↗
PubMed2005

Current status of cellular therapy for ischemic heart disease.

Cellular therapy for acute myocardial infarction and ischemic cardiomyopathy has entered clinical trials across the globe. Early promising results have now provided the justification for larger randomized and blinded trials to address the efficacy of cellular therapy. A variety of fresh or cultured autologous cells have been delivered by catheter-guided endocardial, catheter-guided intracoronary, catheter-guided transvenous, and direct epicardial routes. This review will summarize the clinical data and highlight salient basic science data that support the ongoing efforts to identify the optimal cellular therapy both for acute myocardial infarction and chronic ischemic cardiomyopathy patients.

Bone Marrow Cells↗
PubMed2005

Heart cell implantation after myocardial infarction.

In the last 15 years, heart cell implantation to regenerate infarcted myocardium has gone from the bench to clinical trial. Several phase I and II controlled randomized trials showed the feasibility, the side effects and the potential efficacy of cell implantation after myocardial infarction in humans. Preclinical experiments investigating the mechanisms of heart function improvement after cell implantation showed controversial results regarding implanted cell differentiation into cardiomyocytes and highlighted other effects including neovascularization and modifications of the extra cellular matrix remodelling. Ongoing clinical and experimental studies should pave the way for cell implantation to become a therapeutic option to prevent and treat post-myocardial infarction congestive heart failure in a near future.

Animals↗
PubMed2004

Invited commentary.

Explore the source record for details and available documents.

Coronary Artery Bypass, Off-Pump↗
PubMed2004

Neovascularization derived from cell transplantation in ischemic myocardium.

Myocardial ischemia triggers a limited angiogenic response, part of the remodeling process that is insufficient to avoid further functional impairment. Several strategies have been evaluated to regenerate myocardial vascularization after ischemic injury such as transmyocardial laser revascularization and gene therapy. Attention has recently been focused on the potential of cell therapy to induce angiogenesis. Enhancing myocardial neovascularization is a major goal of myocardial cell transplantation because it would provide patients, who cannot undergo conventional revascularization, with an alternative therapy. Additionally, neovascularization would provide the implanted cells with adequate microenvironment to enhance survival and function. This short review gives an overview of the effect of various cell transplantation strategies on myocardial neovascularization. It suggests that in order to optimize myocardial neovascularization induced by cell therapy, future experiments should focus on the contribution of exogenous and endogenous stem cells to new vessels formation, and on the identification of the molecular pathways involved in the process.

Animals↗