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Noel M Caplice

Publications and source records attributed to Noel M Caplice.

32 records · Page 2Linked to original sources
PubMed2004

Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis.

Lipoprotein(a) (Lp[a]) continues to be a controversial molecule regarding its role in human vascular disease. Although the physiologic role of this molecule is still unclear, novel discoveries within the last few years have suggested numerous mechanisms whereby Lp(a) may contribute to atherosclerosis and its complications in human subjects. These effects may differentially occur in vascular tissue and circulating blood compartments. A complex interplay between tissue-specific effects is probably more relevant to the pathogenicity of this molecule than one single effect alone. This review briefly describes the structure of Lp(a) in relation to its biochemical function, summarizing the current literature on various pathophysiologic mechanisms of Lp(a)-induced vascular disease and the role of cell and tissue-specific effects in promoting atherogenesis and thrombosis.

Arteriosclerosis↗
PubMed2004

Smooth muscle progenitor cells in vascular disease.

Vascular smooth muscle cells have long been described as phenotypically diverse, with some populations possessing the potential for monoclonal expansion within the adult vessel wall. Recent experimental and human data suggest a potential role in atherosclerotic plaque, transplant arteriopathy, and angiogenesis biology for putative smooth muscle progenitor cells in the circulation, adult tissues, and the perivascular adventitia. The location, mobilization, and function of such progenitors is still poorly understood, but may include reparative or alternatively proliferative consequences for plaque development and progression. These observations provide a platform for re-evaluation of smooth muscle cell heterogeneity and progenitor biology in atherosclerosis, with implications for diagnosis and therapy of vascular disease.

Animals↗
PubMed2004

Myocardial-cell replacement: the science, the clinic and the future.

The traditional view of the heart is of an organ incapable of self-renewal. Hypotheses on the genesis of pump dysfunction in heart failure include emerging concepts of myocyte deficiency due to attritional ischemia and chronic apoptotic cell loss. In the adult heart, inadequate regenerative capacity was presumed to exist to counterbalance such extensive myocyte depletion. Preliminary animal and human studies now challenge the paradigm of myocardial regenerative inadequacy, with findings suggesting that noncardiac cells implanted in the dysfunctional heart augment myocyte deficiency and contractile mass. Data from these studies remain inconclusive and have generated much debate in the basic science and clinical communities. Controversial issues center on the scientific basis for regeneration in the heart, the mechanism of cell-therapy benefit and the safety and appropriateness of clinical trials based on these concepts. This review will evaluate the scientific basis for myocardial-cell replacement, with emphasis on current experimental and human data. We will explore unresolved questions of experimental design, mechanism of action, therapeutic strategies and safety concerns in an era of rising numbers of human cell-therapy trials. Prospects for more widespread clinical application of myocardial-cell replacement and future hurdles to be overcome in this field will also be addressed.

Animals↗
PubMed2004

Fatal coronary artery disease after unrelated donor bone marrow transplantation.

Several factors are responsible for the occurrence of cardiac complications after bone marrow transplantation (BMT). These factors include the cardiotoxic effects of radiation therapy, antineoplastic and immunosuppressive drugs, abnormal immunologic reactions associated with graft-vs-host disease, and infectious agents. We report the case of a 45-year-old woman with T-cell prolymphocytic leukemia and no prior risk factors for coronary artery disease in whom sudden cardiac death occurred 2 1/2 years after allogeneic BMT from an unrelated male donor. Autopsy revealed severe 3-vessel coronary disease with grade 4/4 stenosis. This process was primarily nonatherosclerotic, with intimal hyperplasia of undetermined etiology. Furthermore, fluorescence in situ hybridization to identify the donor Y chromosome with simultaneous immunofluorescence labeling of smooth muscle actin suggested the presence of donor cells that transformed into myocytes. Coronary artery disease is an important, albeit rare, complication of BMT. Donor hematopoietic cells may contribute to its pathogenesis.

Bone Marrow Transplantation↗
PubMed2003

Nitric oxide synthase gene transfer as a tool to study biology of endothelial cells.

During the past decade, the development of gene transfer technology provided a powerful and facile tool that afforded the genetic modification of vascular endothelial function. This development has coincided with molecular cloning and extensive accumulation of knowledge concerning the role of nitric oxide synthase isoforms in vascular homeostasis. Experimental evidence continues to accumulate that in vivo adenovirus-mediated gene transfer into the vessel wall is a very useful technique in studies designed to characterize function of a given gene or protein. In this review, we will use nitric oxide synthase gene transfer as a paradigm to illustrate how gene transfer technology can be used to address key issues in the vascular biology of endothelium.

Animals↗
PubMed2003

Endothelial progenitor cells are decreased in blood of cardiac allograft patients with vasculopathy and endothelial cells of noncardiac origin are enriched in transplant atherosclerosis.

BACKGROUND: Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation. METHODS AND RESULTS: Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFUEPC]: 4.5+/-1.9 versus 15.1+/-3.7, P<0.05). There was no significant difference in circulating endothelial cell numbers as defined by day 4 culture acetylated LDL/lectin assay in either of these patient groups. In a separate group of 5 subjects who underwent gender-mismatched cardiac transplantation, there was a significant seeding of recipient endothelial cells (range: 1% to 24% of all luminal endothelial cells) in large-vessel lumen and adventitial microvessel lumen of arteriopathic vessels. No opposite-sex chimeric cells were observed in control gender-matched transplantation scenarios. CONCLUSIONS: These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.

Adult↗
PubMed2003

Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation.

Atherosclerosis is the major cause of adult mortality in the developed world, and a significant contributor to atherosclerotic plaque progression involves smooth muscle cell recruitment to the intima of the vessel wall. Controversy currently exists on the exact origin of these recruited cells. Here we use sex-mismatched bone marrow transplant subjects to show that smooth muscle cells throughout the atherosclerotic vessel wall can derive from donor bone marrow. We demonstrate extensive recruitment of these cells in diseased compared with undiseased segments and exclude cell-cell fusion events as a cause for this enrichment. These data have broad implications for our understanding of the cellular components of human atherosclerotic plaque and provide a potentially novel target for future diagnostic and therapeutic strategies.

Adult↗
PubMed2003

Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients.

BACKGROUND: Recent studies have identified cardiomyocytes of extracardiac origin in transplanted human hearts, but the exact origin of these myocyte progenitors is currently unknown. METHODS AND RESULTS: Hearts of female subjects (n=4) who had undergone sex-mismatched bone marrow transplantation (BMT) were recovered at autopsy and analyzed for the presence of Y chromosome-positive cardiomyocytes. Four female gender-matched BMT subjects served as controls. Fluorescence in situ hybridization (FISH) for the Y chromosome was performed on paraffin-embedded sections to identify cells of bone marrow origin with concomitant immunofluorescent labeling for alpha-sarcomeric actin to identify cardiomyocytes. A total of 160 000 cardiomyocyte nuclei were analyzed approximating 20 000 nuclei per patient. The mean percentage of Y chromosome-positive cardiomyocytes in patients with sex-mismatched BMT was 0.23+/-0.06%. Not a single Y chromosome-positive cardiomyocyte was identified in any of the control patients. Immunofluorescent costaining for laminin and chromosomal ploidy analysis with FISH showed no evidence of either pseudonuclei or cell fusion in any of the chimeric cardiac myocytes identified. CONCLUSIONS: These data establish for the first time human bone marrow as a source of extracardiac progenitor cells capable of de novo cardiomyocyte formation.

Actins↗
PubMed2003

Tissue factor pathway inhibitor deficiency enhances neointimal proliferation and formation in a murine model of vascular remodelling.

Tissue factor (TF) is a small-molecular-weight glycoprotein that initiates the extrinsic coagulation pathway but may have important noncoagulation vascular functions as well. Tissue factor pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. Enhancement of vascular TFPI either by overexpression using gene transfer or delivery of protein to the vessel has been shown to reduce neointimal formation. However, the inherent role of TFPI in this process has not been defined. To do so, we utilized a murine model of vascular remodeling using flow cessation in mice, which are heterozygous for a genetic deletion of the first Kunitz domain of TFPI or wild type littermates. The heterozygotic mice had 50% of wild type TFPI activity in plasma as well as vascular homogenates. To study the effect of TFPI deficiency on neointimal formation, age matched TFPI(K1)+/- and wildtype littermates underwent unilateral common carotid artery ligation. Mice were sacrificed at 4 weeks and the ligated carotid arteries were analyzed. There was a significantly greater neointima to media ratio and less luminal area in the TFPI(K1)+/- mice compared to their TFPI(K1)+/+ littermates. The proliferative index of intimal cells in TFPI(K1)+/- mice at 1 week was significantly higher compared to TFPI(K1)+/+ mice. We conclude that TFPI deficiency enhances neointimal formation and proliferation associated with flow cessation. This suggests that TFPI may regulate vascular remodeling primarily through modulation of neointimal formation.

Animals↗
PubMed2002

Smooth muscle progenitor cells in human blood.

BACKGROUND: Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells. METHODS AND RESULTS: Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB-enriched medium caused rapid outgrowth and expansion of SOC to >40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell-specific alpha actin (alphaSMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle-specific markers. Integrin alpha5beta1 expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin (P<0.001), an effect that could be decreased using an alpha5beta1 antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage (P<0.001). CONCLUSIONS: This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing.

Adult↗
PubMed2002

A tissue-engineered stent for cell-based vascular gene transfer.

Cell-based gene transfer using a stent platform would provide a significant advantage in terms of site-specific gene expression in the vasculature. The current study presents a novel stent design that allows stable in vivo transgene expression over a 4-week period in the vasculature. A mesh-stent coated with fibronectin provided an excellent platform for adherent porcine smooth muscle cells (SMC). Autologous porcine SMC were stably transduced with a plasmid encoding green fluorescence protein (GFP), seeded at high density in the mesh-stent, and deployed in the porcine coronary artery. Stable in vivo GFP expression within the mesh-stent (5.2 x 10(5) GFP-positive cells/cm(2) mesh) was demonstrated 1 month after implantation in the porcine coronary artery by fluorescence microscopy and flow cytometry. No significant change in GFP positive cell number within the stent occurred over a 1-month period in vivo when compared to preinsertion. Angiographic and histologic analysis revealed mild neointimal proliferation and no inflammatory infiltrate in the stented segment. This study has implications for treatment of cardiovascular and other diseases where long-term cell-based delivery of transgene is a desirable therapeutic option.

Animals↗
PubMed1999

Molecular biology and gene transfer in atherosclerosis in the stenting era.

Atherosclerosis is the major cause of death in the developed world. Understanding the pathogenesis of atherosclerosis has been a major challenge to cardiovascular research over the past several decades. During this period a number of advances in various scientific disciplines has increased our understanding of this disease. These include improved understanding of the structural and functional components of normal vessel wall and more recently the use of cell biology and molecular biology techniques to elucidate the pathogenesis of atherosclerosis. None of these advances has been more dramatic nor has potentially more far reaching consequences as the application of molecular biology and gene technology to the practice of cardiovascular medicine. These developments have already opened new and exciting areas of vascular research and may in the future provide for earlier identification of genetic predisposition to atherosclerosis, strategic planning of preventive therapy and more tailored pharmacologic approaches for established disease.

Journal Article↗
PubMedDate not supplied

Endothelial progenitor cells.

The identification of circulating endothelial progenitor cells (EPCs) has prompted an explosion of interest in postnatal vasculogenesis and the role of this mechanism in human health and disease. Previously considered restricted to the embryonic phase, the differentiation in situ of progenitor cells to vascular endothelium is now known to occur in the adult. A role for EPCs in the modulation of angiogenesis has also been recognized. These cells are enriched in the mononuclear cell fraction of peripheral blood but have also been isolated from bone marrow, the vessel wall, and a number of other organs and tissues. Accumulating data suggest an important vasculoprotective function for EPCs, although a maladaptive role underpinning a variety of angiogenesis-dependent diseases is also being investigated. Encouraging results observed with experimental and early human trials of EPC-based regenerative therapies have further underscored the significance of this recently discovered cell type. Notwithstanding the scope and pace of these developments, a number of challenges remain: the precise ontogeny and lineage of these cells is unknown, the true extent to which EPCs participate in neovascularization and vascular repair is still uncertain, and the efficacy of EPC-based regenerative therapies has yet to be proven in randomized controlled trials.

Cell Lineage↗