Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin.

Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration.

A role of matrix metalloproteinase-8 in atherosclerosis.

Rationale: Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I.

Objective: We studied whether MMP8 plays a role in atherogenesis.

Methods And Results: In atherosclerosis-prone apolipoprotein E-deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation.

Single nucleotide polymorphism on chromosome 9p21 and endothelial progenitor cells in a general population cohort.

Objective: Recent studies have revealed that sequence variation on chromosome 9p21 is a major genetic determinant for coronary heart disease and stroke, however, the underlying mechanism remains unknown. This genomic region contains the gene encoding cyclin-dependent kinase 2A, a regulator of proliferation and differentiation of endothelial progenitor cell (EPC) which has been implicated in vascular repair and protection against cardiovascular disease. We investigated whether carriers and non-carriers of the chromosome 9p21 variation differed in their number and function of EPCs.

PGC-1alpha attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery.

Oxidative stress contributes significantly to the migration of vascular smooth muscle cells (VSMCs), the major pathogenic process of vascular diseases, but the mechanism remains unclear. In the present study, we explored the role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a major regulator of mitochondrial biogenesis and energy balance, in VSMC migration in vitro and in vivo. Overexpression of PGC-1alpha in cultured VSMCs led to a 74.

Regulatory T cells ameliorate hyperhomocysteinaemia-accelerated atherosclerosis in apoE-/- mice.

Aims: Atherosclerosis is an inflammatory disease with T cell-driven immunoinflammatory responses contributing to disease initiation and progression. We investigated the potential role of regulatory T cells (Tregs) in hyperhomocysteinaemia (HHcy)-accelerated atherosclerosis in apoE-/- mice.

Methods And Results: apoE-/- mice were fed normal mouse chow supplemented with or without a high level of homocysteine (Hcy) (1.

Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow.

X-box binding protein 1 (XBP1) is a key signal transducer in endoplasmic reticulum stress response, and its potential role in the atherosclerosis development is unknown. This study aims to explore the impact of XBP1 on maintaining endothelial integrity related to atherosclerosis and to delineate the underlying mechanism. We found that XBP1 was highly expressed at branch points and areas of atherosclerotic lesions in the arteries of ApoE(-/-) mice, which was related to the severity of lesion development.

Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures.

The concept of endothelial progenitor cells (EPCs) has attracted considerable interest in cardiovascular research, but despite a decade of research there are still no specific markers for EPCs and results from clinical trials remain controversial. Using liquid chromatography-tandem mass spectrometry, we analyzed the protein composition of microparticles (MPs) originating from the cell surface of EPC cultures. Our data revealed that the conventional methods for isolating mononuclear cells lead to a contamination with platelet proteins.

Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells.

Histone deacetylases (HDACs) have a central role in the regulation of gene expression. Here we investigated whether HDAC7 has an impact on embryonic stem (ES) cell differentiation into smooth muscle cells (SMCs). ES cells were seeded on collagen-IV-coated flasks and cultured in the absence of leukemia inhibitory factor in differentiation medium to induce SMC differentiation.

ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries.

The migration of vascular smooth muscle cells (VSMCs) plays an essential role during the development of atherosclerosis and restenosis. Extensive studies have implicated the importance of extracellular matrix (ECM)-degrading proteinases in VSMC migration. A recently described family of proteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), is capable of degrading vascular ECM proteins.

SDF1 gene variation is associated with circulating SDF1alpha level and endothelial progenitor cell number: the Bruneck Study.

Background: Stromal cell-derived factor-1 (SDF1) and its receptor CXC chemokine receptor 4 (CXCR4) play a critical role in progenitor cell homing, mobilization and differentiation. It would be interesting to assess the predictive value of SDF-1alpha level for EPC number, and to ascertain whether there is a relationship between SDF1 gene variation, plasma SDF-1alpha level, and the number and function of circulating EPCs. We also tested whether EPC number and function was related to CXCR4 gene variation.

Asymmetric and symmetric dimethylarginines are of similar predictive value for cardiovascular risk in the general population.

Objectives: Asymmetric dimethylarginine (ADMA) has raised considerable interest, as it is an endogenous inhibitor of nitric oxide synthesis. While increased plasma levels of ADMA have been reported in different cardiovascular disease states, its association with symmetric dimethylarginine (SDMA) has not been evaluated in a prospective population-based study.

Methods And Results: We performed a mass spectrometry-based analysis of ADMA and SDMA in the plasma of 572 participants of the Bruneck study.

Rheological effects of blood in a nonplanar distal end-to-side anastomosis.

This study investigates rheological effects of blood on steady flows in a nonplanar distal end-to-side anastomosis. The shear-thinning behavior of blood is depicted by a Carreau-Yasuda model and a modified power-law model. To explore effects of nonplanarity in vessel geometry, a curved bypass graft is considered that connects to the host artery with a 90 deg out-of-plane curvature.

Embryonic stem cell differentiation into smooth muscle cells is mediated by Nox4-produced H2O2.

NADPH oxidase (Nox4) produces reactive oxygen species (ROS) that are important for vascular smooth muscle cell (SMC) behavior, but the potential impact of Nox4 in stem cell differentiation is unknown. When mouse embryonic stem (ES) cells were plated on collagen IV-coated dishes/flasks, a panel of SMC-specific genes was significantly and consistently upregulated. Nox4 expression was markedly correlated with such a gene induction as confirmed by real-time PCR, immunofluorescence, and Western blot analysis.

Proteomic and metabolomic analysis of cardioprotection: Interplay between protein kinase C epsilon and delta in regulating glucose metabolism of murine hearts.

We applied a combined proteomic and metabolomic approach to obtain novel mechanistic insights in PKCvarepsilon-mediated cardioprotection. Mitochondrial and cytosolic proteins from control and transgenic hearts with constitutively active or dominant negative PKCvarepsilon were analyzed using difference in-gel electrophoresis (DIGE). Among the differentially expressed proteins were creatine kinase, pyruvate kinase, lactate dehydrogenase, and the cytosolic isoforms of aspartate amino transferase and malate dehydrogenase, the two enzymatic components of the malate aspartate shuttle, which are required for the import of reducing equivalents from glycolysis across the inner mitochondrial membrane.

Proteomics identifies thymidine phosphorylase as a key regulator of the angiogenic potential of colony-forming units and endothelial progenitor cell cultures.

Endothelial progenitor cell (EPC) cultures and colony-forming units (CFUs) have been extensively studied for their therapeutic and diagnostic potential. Recent data suggest a role for EPCs in the release of proangiogenic factors. To identify factors secreted by EPCs, conditioned medium from EPC cultures and CFUs was analyzed using a matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometer combined with offline peptide separation by nanoflow liquid chromatography.

Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study.

Aims: To identify factors that influence plasma levels and assess the prognostic value of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in a prospective, population-based survey of the epidemiology and pathogenesis of atherosclerosis.

Methods And Results: The Bruneck study is a prospective, population-based survey initiated in 1990. Lp-PLA2 activity and baseline variables for the current analysis were measured in 765 subjects aged 45-84 years in 1995.

Regulatory role of thioredoxin in homocysteine-induced monocyte chemoattractant protein-1 secretion in monocytes/macrophages.

We have previously shown that homocysteine (Hcy) can induce monocyte chemoattractant protein-1 (MCP-1) secretion via reactive oxygen species (ROS) in human monocytes. Here, we show that Hcy upregulates expression of an important antioxidative protein, thioredoxin (Trx), via NADPH oxidase in human monocytes in vitro. The increase of Trx expression and activity inhibited Hcy-induced ROS production and MCP-1 secretion.

Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study.

Objectives: Following the recent novel finding from genomewide association studies that sequence variation on chromosome 9p21 is a genetic factor for coronary artery disease, we investigated whether the genetic variant influenced the development of atherosclerosis and its progression in a population-based, prospective study.

Background: Recently, several genomewide association studies revealed a highly significant association between variation on chromosome 9p21 and risk of coronary artery disease.

Methods: We studied the rs1333049 polymorphism located on chromosome 9p21 in a cohort of 769 individuals who participated in the Bruneck study with long-term follow-up data on carotid atherosclerosis measured by high-resolution duplex ultrasound and incident cardiovascular disease.

Stem cells and transplant arteriosclerosis.

Stem cells can differentiate into a variety of cells to replace dead cells or to repair damaged tissues. Recent evidence indicates that stem cells are involved in the pathogenesis of transplant arteriosclerosis, an alloimmune initiated vascular stenosis that often results in transplant organ failure. Although the pathogenesis of transplant arteriosclerosis is not yet fully understood, recent developments in stem cell research have suggested novel mechanisms of vascular remodeling in allografts.

Common CCR5-del32 frameshift mutation associated with serum levels of inflammatory markers and cardiovascular disease risk in the Bruneck population.

Background And Purpose: Atherosclerosis is a progressive inflammatory disease and can develop in large arteries such as carotid and femoral arteries or medium-sized muscular arteries of the heart. Previous predominantly experimental studies suggested an important role of chemokines in the development of atherosclerosis. The main aim of this study was to examine potential effect of the CCR5-del32 mutation on systemic inflammation, intima-media thickness in carotid and femoral arteries, and on the indices of cardiovascular disease.

Proteomic and metabolomic analysis of smooth muscle cells derived from the arterial media and adventitial progenitors of apolipoprotein E-deficient mice.

We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic approach, we now characterize these local progenitors, which participate in the formation of native atherosclerotic lesions in chow-fed apoE(-/-) mice. Unlike Sca-1(+) progenitors from embryonic stem cells, the resident Sca-1(+) stem cell population from the vasculature acquired a mature aortic SMC phenotype after platelet-derived growth factor-BB stimulation.