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Biomedical subjects

Subodh Verma

Publications and source records attributed to Subodh Verma.

At least 73 records · Page 4Linked to original sources
PubMed2004

Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists inhibit vascular smooth muscle proliferation and migration and improve endothelial function. It is unknown whether PPAR-gamma agonists favorably modulate bone marrow (BM)-derived angiogenic progenitor cells (APCs) to promote endothelial lineage differentiation and early reendothelialization after vascular intervention. METHODS AND RESULTS: C57/BL6 mice, treated with or without rosiglitazone (8 mg/kg per day), a PPAR-gamma agonist, underwent femoral angioplasty. Rosiglitazone treatment attenuated neointimal formation (intima/media ratio: 0.98+/-0.12 [rosiglitazone] versus 3.1+/-0.5 [control]; P<0.001; n=10 per group). Using a BM transplantation model, we identified that 58+/-12% of the cells within the neointima at 4 weeks were derived from the BM. Pure endothelial marker-positive, pure alpha-smooth muscle actin (alphaSMA)-positive, or double-positive APCs could be found both in mouse BM and in human peripheral blood after culture in conditional medium enriched with vascular endothelial growth factor. Rosiglitazone caused a 6-fold (P<0.001) increase in colony formation by human endothelial progenitor cells, promoted the differentiation of APCs toward the endothelial lineage in mouse BM in vivo (0.66+/-0.06% [control] to 0.95+/-0.08% [rosiglitazone]; P<0.05) and in human peripheral blood in vitro (13.2+/-1.5% [control] to 28.4+/-3.3% [rosiglitazone]; P<0.05), and inhibited the differentiation toward the smooth muscle cell lineage. Within the neointima, rosiglitazone also stimulated APCs to differentiate into mature endothelial cells and caused earlier reendothelialization compared with controls (31+/-5 versus 8+/-2 CD31-positive cells per millimeter of neointimal surface on day 14; P<0.01). CONCLUSIONS: Similar to embryonic stem cell-derived progenitors, the adult BM and peripheral blood harbor APCs that are at least bipotential and able to differentiate into endothelial and smooth muscle lineages. The PPAR-gamma agonist rosiglitazone promotes the differentiation of these APCs toward the endothelial lineage and attenuates restenosis after angioplasty.

Angioplasty↗
PubMed2004

C-reactive protein upregulates complement-inhibitory factors in endothelial cells.

BACKGROUND: Because complement-mediated vascular injury participates in atherosclerosis and C-reactive protein (CRP) can activate the complement cascade, we sought to determine whether CRP affects the expression of the protective complement-inhibitory factors on the cell surface of endothelial cells (ECs). METHODS AND RESULTS: Human coronary artery or human saphenous vein ECs were incubated with CRP (0 to 100 microg/mL, 0 to 72 hours), and the expression of the complement-inhibitory proteins decay-accelerating factor (DAF), membrane cofactor protein (CD46), and CD59 were measured by flow cytometry. Incubation with CRP resulted in a significant increase in the expression of all 3 proteins. CRP-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. The increased expression of complement-inhibitory proteins was functionally effective, resulting in significant reduction of complement-mediated lysis of antibody-coated human saphenous vein ECs. CONCLUSIONS: These observations provide evidence for a possible protective role for CRP in atherogenesis.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2004

Cross-sectional evaluation of brachial artery flow-mediated vasodilation and C-reactive protein in healthy individuals.

AIMS: The present study was designed to (a) examine the interrelationship between endothelial function and CRP in healthy individuals and (b) evaluate the relationship of each biomarker towards global Framingham risk scores. METHODS AND RESULTS: Brachial artery flow-mediated vasodilatation (FMD), CRP, and traditional cardiovascular risk factors were measured in the Firefighters and Their Endothelium (FATE) study, which recruited 1154 male participants (mean age 47.4+/-9.8 years) with no known history of cardiovascular disease. No relationship was observed between FMD and CRP (p = 0.96). FMD and the Framingham risk score tended to correlate but not significantly (p = 0.07). A lower FMD was related to a higher systolic and diastolic blood pressure (p < 0.001 and p = 0.002, respectively) in the univariate analysis, and higher systolic blood pressure (p = 0.001) in the multivariate analysis. Elevated CRP levels independently correlated most closely with overall Framingham risk score (r = 0.36, p < 0.001) and a weaker although statistically significant relationship was seen with individual traditional cardiovascular risk factors (p < 0.005). CONCLUSIONS: The current study provided evidence that brachial artery FMD had no relationship to CRP in a large cohort of healthy subjects. These observations suggest that the predictive value of CRP may be largely independent of abnormalities in endothelial function. The additive prognostic value of endothelial vasodilator testing remains to be established.

Blood Flow Velocity↗
PubMed2004

Insulin resistance as a therapeutic target for improved endothelial function: metformin.

Endothelial dysfunction is a feature of a variety of clinical states of insulin resistance, and increasingly it is recognized that pre-diabetic states of insulin resistance are associated not only with insulin resistance but with increased cardiovascular risk. The metabolic syndrome which typically accompanies insulin resistance brings aberrations in a number of classical cardiovascular risk factors, but it appears that insulin resistance itself represents an additional, non-classical risk factor. Therefore, the approach to treating the endothelium in patients with the metabolic syndrome might include therapies targeting insulin resistance. In this review, we provide a detailed overview of the current state of knowledge regarding the biguanide metformin and its effects on the endothelium. Its mode of action is reviewed, along with the available data from laboratory and experimental studies related to vascular function in animals and in humans. Metformin has beneficial effects on endothelial function which appear to be mediated through its effects to improve insulin resistance. Therapeutically targeting insulin resistance appears to be a viable route to improving endothelial function in clinical states of insulin resistance.

Animals↗
PubMed2004

C-reactive protein incites atherosclerosis.

Accumulating evidence suggests that C-reactive protein (CRP) levels are a robust and independent predictor of future cardiovascular events. By the same token, increasing data point toward a proatherogenic role of CRP. The present review outlines some of the emerging data that suggest that CRP may directly promote the development of endothelial dysfunction, by affecting endothelium-derived contracting and relaxing factors such as nitric oxide, endothelin, angiotensin and interleukin-6. More recently, CRP has been demonstrated to inhibit the survival and differentiation of bone marrow-derived endothelial progenitor cells, which play a key role in postnatal neovascularization.

Biomarkers↗
PubMed2004

Endothelial function: ready for prime time?

The strategic location of the endothelium allows it to detect changes in hemodynamic forces and blood-borne signals, and to respond by releasing a number of autocrine and paracrine substances. The balanced release of these bioactive factors facilitates vascular homeostasis. If disrupted, endothelial cell dysfunction ensues. This predisposes the vessel wall to vasoconstriction, leukocyte adherence, platelet activation, thrombosis, vascular inflammation and atherosclerosis. Given the central role of the endothelium in the development and progression of atherosclerosis, endothelial function testing may serve as a useful biomarker of atherosclerotic disease. The present review highlights the current modalities used in assessing endothelial function, explores how endothelial function may serve as a biomarker for atherosclerosis, comments on the prognostic relevance of endothelial function and describes its use in the clinical setting.

Biomarkers↗
PubMed2004

Rationale and design of the Glitazones and the Endothelium (GATE) study: evaluation of rosiglitazone on endothelial function in patients with diabetes.

The vascular endothelium has emerged as a critical determinant of cardiovascular health and disease, and improving endothelial function is an important target for therapy. Accumulating evidence suggests that insulin resistance in patients with diabetes and the metabolic syndrome may impair endothelial function, uncovering a proinflammatory, proatherosclerotic vascular phenotype. The rationale and design of the Glitazones and the Endothelium (GATE) study is presented. The GATE study is a randomized, double-blind study for the evaluation of the effects of rosiglitazone versus placebo on endothelial function when used as an add-on therapy in patients with diabetes currently treated with oral therapy. It is hypothesized that the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone will improve endothelium-dependent vasodilation, and that this effect will be related to improvements in insulin sensitivity, with concomitant reductions in whole-body insulin resistance. Furthermore, the beneficial effects of rosiglitazone will be additive to those of existing oral therapies that may modulate endothelial function. Because endothelial dysfunction plays a pivotal role in the development and progression of atherosclerosis, the GATE study may provide the rationale and impetus for the aggressive treatment of insulin-resistant patients with glitazone therapy.

Administration, Oral↗
PubMed2003

Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction.

BACKGROUND: Adipocyte-derived hormones may represent a mechanism linking insulin resistance to cardiovascular disease. In the present study, we evaluated the direct effects of resistin, a novel adipocyte-derived hormone, on endothelial activation. METHODS AND RESULTS: Endothelial cells (ECs) were incubated with human recombinant resistin (10 to 100 ng/ML, 24 hours), and endothelin-1 (ET-1) release, ET-1 mRNA expression, and nitric oxide (NO) production were assessed. Transient transfection assays were used to evaluate the effects of resistin on transcription of human ET-1 gene promoter. Furthermore, the effects of resistin on AP-1-mutated ET-1 promoter were evaluated. The effects of resistin on expression of vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant chemokine (MCP-1) were studied in addition to CD40 receptor, CD40 ligand-induced MCP-1 expression, and tumor necrosis factor receptor-associated factor-3 (TRAF3), an inhibitor of CD40 signaling. Incubation of ECs with resistin resulted in an increase in ET-1 release and ET-1 mRNA expression, with no change in NO production. Whereas treatment with resistin resulted in an increase in ET-1 promoter activity, the AP-1-mutated promoter was inactive after resistin stimulation. Additionally, resistin-treated cells showed increased expression of VCAM-1 and MCP-1, with concomitant reductions in TRAF-3 expression. Resistin did not alter CD40 receptor expression; however, increased CD40 ligand induced MCP-1 production. CONCLUSIONS: The novel adipokine resistin exerts direct effects to promote EC activation by promoting ET-1 release, in part by inducing ET-1 promoter activity via the AP-1 site. Furthermore, resistin upregulates adhesion molecules and chemokines and downregulates TRAF-3, an inhibitor of CD40 ligand signaling. In this fashion, resistin may be mechanistically linked to cardiovascular disease in the metabolic syndrome.

Adipocytes↗
PubMed2003

C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle.

BACKGROUND: Accumulating evidence suggests that C-reactive protein (CRP), in addition to predicting vascular disease, may actively facilitate lesion formation by inciting endothelial cell activation. Given the central importance of angiotensin type 1 receptor (AT1-R) in the pathogenesis of atherosclerosis, we examined the effects of CRP on AT1-R expression and kinetics in vascular smooth muscle (VSM) cells. In addition, the effects of CRP on VSM migration, proliferation, and reactive oxygen species (ROS) production were evaluated in the presence and absence of the angiotensin receptor blocker, losartan. Lastly, the effects of CRP (and losartan) on neointimal formation were examined in vivo in a rat carotid angioplasty model. METHODS AND RESULTS: The effects of human recombinant CRP (0 to 100 microg/mL) on AT1-R transcript, mRNA stability, and protein expression were studied in cultured human VSM cells. AT1-R binding was assessed with 125I-labeled angiotensin II (Ang II). VSM migration was assessed with wound cell migration assays, whereas VSM proliferation was determined with [3H]-incorporation and cell number. The effects of CRP (and losartan) on Ang II-induced ROS production were evaluated by 2',7'-dichlorofluorescein fluorescence. Lastly, the effects of CRP (and losartan) on neointimal formation, VSM cell migration, proliferation, and matrix formation were studied in vivo in a rat carotid artery balloon injury model. CRP markedly upregulated AT1-R mRNA and protein expression and increased AT1-R number on VSM cells. CRP promoted VSM migration and proliferation in vitro and increased ROS production. Furthermore, CRP potentiated the effects of Ang II on these processes. In the rat carotid artery angioplasty model, exposure to CRP resulted in an increase in cell migration and proliferation, collagen and elastin content, and AT1-R expression, as well as an increase in neointimal formation; these effects were attenuated by losartan. CONCLUSIONS: CRP, at concentrations known to predict cardiovascular events, upregulates AT1-R-mediated atherosclerotic events in vascular smooth muscle in vitro and in vivo. These data lend credence to the notion that CRP functions as a proatherosclerotic factor as well as a powerful risk marker.

Angioplasty, Balloon↗
PubMed2003

Genetic abnormalities of the endothelium.

Endothelial cell dysfunction plays an important role in the development and progression of cardiovascular and other disease. The purpose of this review is to discuss some of the genetic diseases known to adversely affect endothelial function. Although the list is exhaustive, we focus our discussion on primary pulmonary hypertension, diabetes mellitus, Alzheimer's disease, Crohn's disease, Von-Hippel-Lindau disease, familial Mediterranean fever, thrombotic microangiopathy, and key vascular malformations. Endothelial dysfunction results from a complex interplay between genetic and environmental factors. This review highlights some of the growing body of evidence implicating endothelial dysfunction as an important mediator of diverse diseases.

Alzheimer Disease↗