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Biomedical subjects

Mark S Segal

Publications and source records attributed to Mark S Segal.

14 recordsLinked to original sources
PubMed2005

A novel mouse model of autologous venous graft intimal hyperplasia.

BACKGROUND: To investigate the molecular mechanism of autologous venous graft intimal hyperplasia, a mouse model is needed. Currently only vein to carotid artery mouse models are available and are hampered by a high thrombosis rate. We hypothesized that operating on the aorta would lead to intimal hyperplasia with decreased risk of thrombosis. MATERIALS AND METHODS: In C57BL/6J mice, the left external jugular vein was grafted into the infrarenal abdominal aorta by end-to-end anastomosis with 11-0 Ethilon. Grafts harvested at 1, 2, 4, 8, and 16 weeks postoperatively were subjected to histological and immunohistochemical analysis. RESULTS: Thirty-one of 35 mice survived; 2 mice were sacrificed secondary to thrombosis. The percentage lumen narrowing (+/-SE) was 7.8 +/- 0.3, 16.4 +/- 0.9, 19.2 +/- 0.9, 22.3 +/- 0.8, and 23.9 +/- 1.6% at 1, 2, 4, 8 and 16 weeks, respectively. Nuclear density decreased with each successive time point. The percentage of alpha-smooth-muscle actin-positive cells within the neointima peaked at 16 weeks (53%), and the percentage of cells positive for proliferating cell nuclear antigen peaked at 2 weeks (39%). CONCLUSIONS: We thus report on a novel mouse model of intimal hyperplasia in autologous venous grafts with a low thrombosis rate. Further studies using this model, coupled with genetic and bone marrow transplantation mouse models, should lead to significant enhancement in understanding of the mechanism of intimal hyperplasia.

Animals↗
PubMed2005

Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?

Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.

Disease Progression↗
PubMed2005

Circulating endothelial cells are associated with future vascular events in hemodialysis patients.

BACKGROUND: Endothelial dysfunction and injury are thought to have a key role in the pathogenesis of cardiovascular disease. We hypothesized that the presence of circulating endothelial cells, as a reflection of ongoing endothelial injury, might provide a novel means for predicting cardiovascular events in hemodialysis subjects who are known to be at marked increased risk for cardiovascular disease. METHODS: Circulating endothelial cell number was determined in 29 hemodialysis patients who were then followed for vascular events for 470 +/- 172 days. In a second cohort of 44 hemodialysis patients, circulating endothelial cell number was correlated with markers of inflammation, namely high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-10, and monocyte chemoattractant protein-1 (MCP-1), and endothelial dysfunction, soluble vascular cellular adhesion molecule-1 (VCAM-1). RESULTS: Seven of the 19 subjects with elevated circulating endothelial cells (defined as >19 cells per mL) had cardiovascular (N= 5) or vascular (N= 5) events during follow-up, whereas no events occurred in subjects with a low number of circulating endothelial cells (</=19 CECs per mL) (P= 0.04 by Fisher Exact Test). In the second cohort, the number of circulating endothelial cells was independent of all markers of inflammation and endothelial dysfunction. CONCLUSION: In this hemodialysis population, an increase in circulating endothelial cells was found to predict the development of cardiovascular and vascular events, and to be independent of other known markers of inflammation or endothelial dysfunction. These studies suggest that circulating endothelial cells may be a novel way to assess endothelial health and cardiovascular risk. Further studies to investigate the utility of circulating endothelial cells in predicting cardiovascular risk are needed.

Adult↗
PubMed2005

SDF-1 is both necessary and sufficient to promote proliferative retinopathy.

Diabetic retinopathy is the leading cause of blindness in working-age adults. It is caused by oxygen starvation in the retina inducing aberrant formation of blood vessels that destroy retinal architecture. In humans, vitreal stromal cell-derived factor-1 (SDF-1) concentration increases as proliferative diabetic retinopathy progresses. Treatment of patients with triamcinolone decreases SDF-1 levels in the vitreous, with marked disease improvement. SDF-1 induces human retinal endothelial cells to increase expression of VCAM-1, a receptor for very late antigen-4 found on many hematopoietic progenitors, and reduce tight cellular junctions by reducing occludin expression. Both changes would serve to recruit hematopoietic and endothelial progenitor cells along an SDF-1 gradient. We have shown, using a murine model of proliferative adult retinopathy, that the majority of new vessels formed in response to oxygen starvation originate from hematopoietic stem cell-derived endothelial progenitor cells. We now show that the levels of SDF-1 found in patients with proliferative retinopathy induce retinopathy in our murine model. Intravitreal injection of blocking antibodies to SDF-1 prevented retinal neovascularization in our murine model, even in the presence of exogenous VEGF. Together, these data demonstrate that SDF-1 plays a major role in proliferative retinopathy and may be an ideal target for the prevention of proliferative retinopathy.

Adrenal Cortex Hormones↗
PubMed2004

The 1.4-MDa apoptosome is a critical intermediate in apoptosome maturation.

Previously, we demonstrated that both 150 mM KCl and alkaline pH inhibit cytochrome c-mediated activation of procaspase-3 in a unique manner. To determine the mechanism of inhibition, we analyzed the effect of KCl and alkaline pH on the formation of apoptosomes (a large complex consisting of cytochrome c, Apaf-1, and procaspase-9/caspase-9) in vitro. Our results suggest that an initial approximately 700-kDa apoptosome matures through a 1.4-MDa intermediate before a approximately 700-kDa apoptosome is reformed and procaspase-3 is activated. We further demonstrate that 150 mM KCl interferes with the conversion of the initial approximately 700-kDa apoptosome to the 1.4-MDa intermediate, while alkaline pH "traps" the apoptosome in the 1.4-MDa intermediate. Analysis of the cleaved state of procaspase-9 and procaspase-3 suggests that the 1.4-MDa intermediate may be required for cleavage of procaspase-9. Consistent with these results, in vivo data suggest that blocking acidification during the induction of apoptosis inhibits activation of procaspase-3. On the basis of these results, we propose a model of apoptosome maturation.

Apoptosis↗
PubMed2004

Thrombotic microangiopathy associated with unusual viral sequences in HIV-1-positive patients.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare disorder caused by endothelial cell damage. TMA has been associated with the human immunodeficiency virus 1 (HIV-1) infection, yet only a minority of all HIV-1 patients develops TMA. Since HIV-1 has been shown to interact with endothelial cells, we investigated whether certain mutations in the HIV-1 envelope protein are associated with the development of TMA in HIV-1-infected patients. METHODS: Plasma was obtained from nine HIV-1-positive patients with TMA. Viral loads were determined from the samples and compared with the clinical data. Viral envelope protein sequences from the regions known to be responsible for viral tropism were isolated, sequenced and compared with known HIV-1 isolates. The isolates were expressed as synthetic fusion proteins; binding of these fusion proteins to CD4+ cells as well as to endothelial cell lines was investigated. RESULTS: The viral loads in patients with HIV/TMA were highly variable with no correlation to the clinical status. Most patients carried macrophage-tropic viral envelope protein sequences and an unusual insertion was found in the V2 variable region. The isolates showed increased CD4 binding, but a direct binding to endothelial cells was not observed. CONCLUSIONS: Although TMA is generally diagnosed in patients with advanced HIV-1 infection, viral loads per se were not predictive of TMA in this study. While a direct interaction with endothelial cells was not detectable, specific viral envelope mutations were found in a region known to influence viral tropism. Hence, viral-specific factors might contribute to the pathogenesis of HIV-associated TMA.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone.

BACKGROUND: Diffuse macular edema (DME) and/or aberrant neovascularization (NV) can cause vision loss in diabetic retinopathy (DR) and may be modulated by growth factors and chemokines. The chemokine stromal-derived factor 1 (SDF-1) is a potent stimulator of vascular endothelial growth factor (VEGF) expression, the main effector of NV, and the key inducer of vascular permeability associated with DME. Circulating endothelial cell precursors migrating in response to SDF-1 participate in NV. OBJECTIVE: To investigate the relationship between SDF-1 and (VEGF) in vitreous of patients with varying degrees of DR and DME before and after intraocular injection of triamcinolone acetonide, used to treat refractory DME. METHODS: In this prospective study, 36 patients were included and observed for 6 months. Vitreous VEGF and SDF-1 levels were measured by enzyme-linked immunosorbent assay in samples obtained immediately before and 1 month after injection of triamcinolone. RESULTS: Both VEGF and SDF-1 were significantly higher (P<.01) in patients with proliferative DR than in patients with nonproliferative DR. Levels of SDF-1 were markedly increased in patients with DME compared with those without DME. Vascular endothelial growth factor correlated with SDF-1 levels and disease severity (r(2) = 0.88). CONCLUSIONS: Triamcinolone administration resulted in dramatic reductions of VEGF and SDF-1 to nearly undetectable levels, eliminated DME, and caused regression of active NV. Our results support a role for SDF-1 and VEGF in the pathogenesis of the adverse visual consequences of DR and suggest that the elimination of DME with regression and/or initiation of fibrosis of NV after triamcinolone injection may be due to the suppression of VEGF and SDF-1.

Aged↗
PubMed2004

Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis.

OBJECTIVE: Lupus nephritis (LN) is a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is evidence that polymorphisms in the genes of inflammatory mediators may predispose to the development of LN in patients with SLE. In this study, we examined the role of a functional monocyte chemoattractant protein 1 (MCP-1) polymorphism in SLE and LN. METHODS: DNA and paired urine and serum samples were obtained from 134 SLE patients (> or =4 American College of Rheumatology criteria for SLE; 49 with and 85 without LN) and 118 controls. MCP-1 genomic variants were detected by polymerase chain reaction followed by restriction enzyme-fragment analysis. Urinary and serum MCP-1 levels and MCP-1 production by peripheral blood macrophages were measured by enzyme-linked immunosorbent assay. RESULTS: The A/A genotype was more common in controls than in SLE patients (P = 0.0002), whereas both the A/G (P = 0.009) and G/G (P = 0.0212) genotypes were more frequent in SLE patients. The A/A genotype was observed in only 23% of the patients with LN compared with 58% of those without LN (P < 0.0001). MCP-1 production by peripheral blood mononuclear cells from patients with the A/G and G/G phenotypes was markedly higher than the production by cells from patients with the A/A genotype. Urinary levels of MCP-1 were significantly higher in patients with LN. CONCLUSION: These results suggest that an A/G or G/G genotype may predispose to the development of SLE and further indicate that SLE patients with these genotypes may be at higher risk of developing LN. Moreover, measurement of urinary levels of MCP-1 may be a useful tool for the detection and management of LN.

Adult↗
PubMed2003

Circulating endothelial cells as potential markers of the state of the endothelium in hemodialysis patients.

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk for atherosclerotic cardiovascular disease (ACVD). In addition to the same epidemiological risk factors of the general population, factors unique or secondary to the uremic milieu may contribute to excess cardiovascular morbidity and mortality. Recent studies suggest the endothelium has a key role in the development of atherosclerosis. Circulating endothelial cells (CECs) may be a tool to study the state of the endothelium, with their number markedly increased in conditions associated with a high degree of endothelial cell activation and/or injury. Our hypothesis is that CEC number increases in diseases that commonly progress to stage 5 CKD, as well as in patients on hemodialysis (HD) therapy, reflecting ongoing endothelial cell activation and/or injury. METHODS: The study population consisted of 22 healthy nonsmoking individuals, 29 individuals undergoing long-term HD treatment, 10 individuals with the diagnosis of diabetes mellitus and stage 1 or 2 CKD, and 7 individuals with hypertension and stage 1 or 2 CKD. The number of CECs was enumerated in all study groups. RESULTS: We found that CEC number was increased in HD patients, hypertensive patients, and patients with diabetes compared with healthy individuals. In addition, although CEC number did not accurately reflect the presence of ACVD, the number was increased significantly in a group of HD patients with active ACVD, whereas it was decreased significantly in a group of HD patients with stable ACVD. CONCLUSION: Our results suggest that CEC number may reflect ACVD activity in HD patients, independent of the presence of ACVD.

Adult↗
PubMed2002

Circulating endothelial cells: tea leaves for renal disease.

Fully differentiated endothelial cells and their precursors circulate in the bloodstream. Since their initial description more than 30 years ago, circulating endothelial cells have been quantified in a number of different clinical conditions that affect the endothelium. Only recently, however, have investigators begun to examine the protein expression and functionality of these cells. Because a number of diseases prevalent in the field of nephrology affect endothelial cells, the study of circulating endothelial cells may allow the direct examination of the state of the endothelium in these conditions. This review will discuss the endothelium and renal disease, the methods to quantify these circulating endothelial cells, their origins, and their therapeutic potential.

Endothelium, Vascular↗
PubMed2002

Marker for real-time analysis of caspase activity in intact cells.

Apoptosis, or programmed cell death, is an important regulator of growth, development, defense, and homeostasis in multicellular organisms. A family of cysteine proteases known as caspases is central to many apoptotic pathways, and thus detection of their activity offers an effective means to assess apoptosis. However, currently available methods only allow the evaluation of in vivo caspase activity at a given time point or over a few hours. To assess the activity over extended periods of time, we designed a novel, real-time, in vivo marker that utilizes the N-end rule degradation pathway to allow the detection of caspase activity as reflected by increasing enhanced GFP (EGFP) stability. The marker has an N-terminal arginine in the absence of caspase activity and is rapidly degraded. In vivo caspase activity removes the marker's N-terminal arginine residue, leaving an EGFP with an N-terminal methionine that results in stable fluorescence. In our study, the marker accurately depicted an increase in caspase activity in apoptotic cells and also detected significant endogenous caspase activity in non-apoptotic cells. The downstream effects of this endogenous activity detected in intact, nonapoptotic cells must be regulated by the cell preventing apoptosis. These studies also demonstrate the feasibility of using the N-end rule to study endogenous enzymatic activities other than those associated with proteasomal degradation.

Apoptosis↗