Acceleration Of Vascular Disease Research Articles

Edetate Disodium-Based Treatment in a Patient With Diabetes and Critical Limb Ischemia After Unsuccessful Peripheral Arterial Revascularizations: A Case Report.

Peripheral artery disease (PAD) is a progressive form of atherosclerosis that affects the lower extremities, particularly in patients with diabetes. Critical limb ischemia (CLI), the end-stage manifestation of this disease, is associated with an increased risk of chronic leg ulcerations, infections, amputations, and mortality. At presentation, 30% of CLI patients require amputation, and 25% will die within 1 year (1). Toxic metal exposure, particularly to cadmium, has been associated with an increased risk of vascular disease in epidemiological studies and PAD severity in patients with coronary artery disease (CAD) (2–4). Toxic metals are ubiquitous and can induce increased oxidative stress, endothelial dysfunction, and inflammation (4). Similarly, chronic cadmium exposure has been found to play a role in the acceleration of vascular disease in animal models (5,6). Edetate disodium is a chelating agent with high affinity for lead and cadmium (7). The Trial to Assess Chelation Therapy (TACT) demonstrated that edetate disodium–based chelation reduced cardiovascular events, especially in patients with diabetes after myocardial infarction (8,9). An 81-year-old man with a 35-year history of insulin-dependent diabetes, a 20 pack-year smoking history (quit date October 2001), atrial fibrillation, and CAD requiring coronary artery bypass in 2001 presented to the vascular service. His medications at baseline included sotalol, rivaroxaban, pentoxifylline, clopidogrel, aspirin, insulin, pregabalin, and atorvastatin. His baseline serum creatinine was 0.77 mg/dL, and his BMI was 22 kg/m2. He had progressive CLI with nonhealing ulcers and pain unimproved by medical therapy. Noninvasive tests demonstrated abnormal ankle-brachial indices bilaterally. Lower-extremity angiography revealed total occlusions of the left external iliac artery, left superficial femoral artery, distal right …

Protein carbamylation: a key driver of vascular calcification during chronic kidney disease

Vascular calcification is a frequent complication of advanced chronic kidney disease. Protein carbamylation is implicated in the acceleration of vascular disease in chronic kidney disease, but the mechanisms are notclear. Mori etal. report that protein carbamylation exacerbates vascular calcification by decreasing ectonucleotide pyrophosphate/phosphodiesterase 1 expression, owing to carbamylation of mitochondrial proteins and oxidative stress. This provides new insight into the pathways responsible for calcification in chronic kidney disease.

Calcium and Cardiovascular Disease.

Circulating calcium is a risk factor for vascular disease, a conclusion arising from prospective studies involving hundreds of thousands of participants and extending over periods of up to 30 years. These associations may be partially mediated by other cardiovascular risk factors such as circulating lipid levels, blood pressure, and body mass index, but there appears to be a residual independent effect of serum calcium. Polymorphisms of the calcium-sensing receptor associated with small elevations of serum calcium are also associated with cardiovascular disease, suggesting that calcium plays a causative role. Trials of calcium supplements in patients on dialysis and those with less severe renal failure demonstrate increased mortality and/or acceleration of vascular disease, and meta-analyses of trials in those without overt renal disease suggest a similar adverse effect. Interpretation of the latter trials is complicated by a significant interaction between baseline use of calcium supplements and the effect of randomisation to calcium in the largest trial. Restriction of analysis to those who are calcium-naive demonstrates a consistent adverse effect. Observational studies of dietary calcium do not demonstrate a consistent adverse effect on cardiovascular health, though very high or very low intakes may be deleterious. Thus, obtaining calcium from the diet rather than supplements is to be encouraged.

Human cytomegalovirus infection and vascular disease risk: A meta-analysis

BackgroundHuman cytomegalovirus (HCMV) infection has been associated with the acceleration of vascular disease. Numbers studies were conducted to analyze the association between HCMV infection and risk of vascular disease, but no clear consensus had been reached. The aim of this study was to confirm this relationship precisely by doing a systematic review and meta-analysis. MethodsWe identified relevant studies through a search of PubMed and Embase. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: (1) evaluating the association between HCMV infection and vascular disease; (2) case-control studies or nested case-control studies; (3) and supply the numbers (or percentage) of positivity for HCMV infection in cases and controls, respectively. Data were extracted and analyzed independently by two investigators. Ultimately, We included data from 68 studies, which altogether enrolled 12027 cases and 15386 controls from 24 countries. ResultsHCMV IgG was detected 7376 in 10611 cases, HCMV IgM was detected 153 in 1486 cases and HCMV DNA was detected 654 in 2139 cases. Overall, people exposed to HCMV infection had higher risk than those not exposed for vascular disease (OR 1.70 [95% CI 1.43–2.03] IgG-based HCMV tests, 2.88 [95% CI 1.87–4.43] IgM-based HCMV tests and 2.56 [95% CI 1.46–4.49 PCR-based HCMV tests]). HCMV infection was clearly identified as a risk factor for vascular disease in Asian group, Caucasian group and other group, especially Asian group(OR 1.86 [95% CI 1.33–2.60] IgG-based HCMV tests, 3.57 [95% CI 1.94–6.60] IgM-based HCMV tests and 4.09 [95% CI 3.10–5.40 PCR-based HCMV tests]). ConclusionThis meta-analysis suggested that HCMV infection is associated with an increased risk for vascular disease.

Glycation of extracellular matrix proteins and its role in atherosclerosis

Glycation consists in formation of advanced glycation end-products (AGE) during non-enzymatic reaction between reducing sugars and proteins, lipids or nucleic acids. This review is focused mainly on glycation of collagen and its role in acceleration of vascular disease. Collagen is an extracellular matrix protein characterized by unique structure forming fibrils with great anti-tensile and anti-breaking strength. The protein builds the connective tissue and is responsible for biomechanical properties of blood vessels. It is reported that higher content of glycated collagen correlates with lower elasticity and greater toughness of the vessel walls and, as a consequence, a faster rate of atherosclerosis development. Numerous mechanisms connected with AGE formation are involved in atherogenesis, among others: receptor-mediated production of free radicals, triggering an inflammatory process, activation of leukocytes and thrombocytes, facilitation of LDL binding, change in level of growth factors, adhesion molecules, MMP and some other proteins' expression. The coverages allow the development of therapeutic strategies to prevent or slow down the pathological processes connected with glycation of collagen and other proteins in the artery wall. The main strategies are based on limitation of exogenous AGE, consumption of products which contain rutin, treatment with drugs which inhibit AGE formation, such as pyridoxamine, and chemicals which are able to cleave already formed AGE protein-protein crosslinks, such as ALT-711.

HCMV pUS28 initiates pro-migratory signaling via activation of Pyk2 kinase

BackgroundHuman Cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease and chronic allograft rejection. Recently, the virus has been associated with glioblastoma and other tumors. We have previously shown that the HCMV-encoded chemokine receptor pUS28 mediates smooth muscle cell (SMC) and macrophage motility and this activity has been implicated in the acceleration of vascular disease. pUS28 induced SMC migration involves the activation of the protein tyrosine kinases (PTKs) Src and Focal adhesion kinase as well as the small GTPase RhoA. The PTK Pyk2 has been shown to play a role in cellular migration and formation of cancer, especially glioblastoma. The role of Pyk2 in pUS28 signaling and migration are unknown.MethodsIn the current study, we examined the involvement of the PTK Pyk2 in pUS28-induced cellular motility. We utilized in vitro migration of SMC to determine the requirements for Pyk2 in pUS28 pro-migratory signaling. We performed biochemical analysis of Pyk2 signaling in response to pUS28 activation to determine the mechanisms involved in pUS28 migration. We performed mass spectrometric analysis of Pyk2 complexes to identify novel Pyk2 binding partners.ResultsExpression of a mutant form of Pyk2 lacking the autophosphorylation site (Tyr-402) blocks pUS28-mediated SMC migration in response to CCL5, while the kinase-inactive Pyk2 mutant failed to elicit the same negative effect on migration. pUS28 stimulation with CCL5 results in ligand-dependent and calcium-dependent phosphorylation of Pyk2 Tyr-402 and induced the formation of an active Pyk2 kinase complex containing several novel Pyk2 binding proteins. Expression of the autophosphorylation null mutant Pyk2 F402Y did not abrogate the formation of an active Pyk2 kinase complex, but instead prevented pUS28-mediated activation of RhoA. Additionally, pUS28 activated RhoA via Pyk2 in the U373 glioblastoma cells. Interestingly, the Pyk2 kinase complex in U373 contained several proteins known to participate in glioma tumorigenesis.ConclusionsThese findings represent the first demonstration that pUS28 signals through Pyk2 and that this PTK participates in pUS28-mediated cellular motility via activation of RhoA. Furthermore, these results provide a potential mechanistic link between HCMV-pUS28 and glioblastoma cell activation.

Elevation of the glycoxidation product Nε-(carboxymethyl)lysine in patients presenting with acute myocardial infarction

An important role in the acceleration of vascular disease has been previously suggested for advanced glycation end products. N(epsilon)-(carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined non-enzymatic glycation and glycoxidation reactions. CML reacts with the receptor of advanced glycation end products inducing impairment of endothelium dependent relaxation and is a marker of oxidative stress. A total of 40 patients with acute myocardial infarction (17 patients with ST-elevation myocardial infarction, 23 patients with non-ST-elevation myocardial infarction) and 40 patients with stable coronary artery disease were included consecutively in this study. During coronary angiography, peripheral venous blood sample was taken for measuring CML. Serum levels of CML were significantly increased in patients with acute myocardial infarction [17.9+/-10.7 vs. 6.6+/-3.1 arbitrary units (AU)/mg protein, p<0.001]. A cut-off value of CML>9.5 AU/mg protein was associated with an odds ratio of acute myocardial infarction of 39.7 [95% confidence interval (CI): 11.1-142, p<0.001], a sensitivity of 0.85 (95% CI: 0.70-0.94) and a specificity of 0.88 (95% CI: 0.73-0.96). CML levels are significantly elevated in patients presenting with acute myocardial infarction. These results suggest the involvement of endothelial dysfunction (through receptor interaction) and oxidative stress in acute myocardial infarction.

Interaction of Nε(carboxymethyl)lysine- and methylglyoxalmodified albumin with endothelial cells and macrophages

In diabetes mellitus an increased risk exists for vascular complications. A role for advanced glycation endproducts (AGEs) in the acceleration of vascular disease has been suggested. Nepsilon-(carboxymethyl)lysine (CML)- and methylglyoxal (MGO)-modified proteins have been identified as major AGEs. The interaction of these AGEs with the human endothelial cells and macrophages was studied. Changes in adhesion molecule expression, i.e. vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin were determined by cell-bound Elisa on human endothelial cells after incubation with CML-modified albumin and MGO-modified albumin. The presence of the full-length receptor of AGEs (RAGE) and splice variants of RAGE was determined by specific RT-PCR. In addition, binding studies were performed with CML- and MGO-modified albumin to endothelial cells and P388D1 macrophages. We demonstrated that CML-albumin or MGO-albumin did not induce activation of endothelial cells as measured by the expression of adhesion molecules, while, under the same conditions, TNF-alpha did. No specific binding of CML-albumin and MGO-albumin on these cells was found. In contrast to endothelial cells, a specific binding of MGO-albumin to P388D1 macrophages was demonstrated, which could be competed by ligands of scavenger receptors. In human umbilical vein and microvascular endothelial cells we found the N-truncated and C-truncated splice variants of RAGE. In conclusion, under our experimental conditions no CML- or MGO-albumin-induced increase in adhesion molecule expression was found on endothelial cells. In agreement with this, no binding of these AGEs was found to endothelial cells. The existence of splice variants of RAGE in endothelial cells might explain the lack of interaction of extracellular AGEs with these cells.

Smoking, Metalloproteinases, and Vascular Disease

Smoking causes up to 11% of total global cardiovascular deaths. Smoking has numerous effects that may promote atherosclerosis through vascular inflammation and oxidative stress, but the pathogenesis of smoking-related cardiovascular disease remains incompletely understood. The matrix metalloproteinases, a family of endopeptidases that can degrade extracellular matrix components in both physiological and pathophysiological states, play an important role in smoking-associated chronic obstructive pulmonary disease, the second leading cause of smoking attributable mortality. Emerging evidence indicates that the matrix metalloproteinases may also contribute to smoking-related vascular disease. Here we discuss the potential relationship between smoking, matrix metalloproteinases, and acceleration of vascular disease.

Atherosclerosis and restenosis: Is there a role for rage?

Diabetic vascular complications are a major cause of morbidity and mortality. Furthermore, such vascular disease is only incompletely explained by "traditional" risk factors in the nondiabetic complications. This situation has prompted the search for factors contributing to the pathogenesis of accelerated and more severe vascular disease in patients with diabetes. We review evidence that receptor for advanced glycation end products (RAGE), via its interaction with ligands, serves as a cofactor exacerbating diabetic vascular disease. RAGE is a member of the immunoglobulin superfamily of cell surface molecules with a diverse repertoire of ligands reminiscent of pattern recognition receptors. In the diabetic milieu, two classes of RAGE ligands, products of nonenzymatic glycoxidation and S100 proteins, appear to drive receptor-mediated cellular activation and, potentially, acceleration of vascular disease.

Do Pathogens Accelerate Atherosclerosis?

Infection with the pathogens human cytomegalovirus (HCMV) or Chlamydia pneumonia (CP) is linked to the development of vascular disease, including atherosclerosis. The role of pathogens in vasculopathies has been controversial. However, animal models have demonstrated a direct link between infection with CP and herpesviruses and the development of vascular disease. Clinical studies have shown a direct association of HCMV and CP with the acceleration of vascular disease. This article will review the evidence supporting the role for CP and HCMV in the development of vascular disease and will suggest a potential mechanism for HCMV acceleration of the disease process. Vascular diseases are the result of either mechanical or immune-related injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and/or migration from the vessel media to the intima, which culminates in vessel narrowing. A number of in vitro and in vivo models have provided potential mechanisms involved in pathogen-mediated vascular disease. Recently, we have demonstrated that HCMV infection of arterial but not venous SMC results in significant cellular migration in vitro. Migration was dependent on expression of the HCMV-encoded chemokine receptors, US28, and the presence of the chemokines, RANTES or MCP-1. Migration involved chemotaxis and provided the first evidence that viruses may induce migration of SMC toward sites of chemokine production through the expression of a virally encoded chemokine receptor in infected SMC. Because SMC migration into the neointimal space is the hallmark of vascular disease, these observations provide a molecular link between HCMV and the development of vascular disease.

Oxidative stress in diabetic macrovascular disease: does homocysteine play a role?

Non-insulin-dependent diabetes mellitus (NIDDM) and hyperhomocysteinemia are both associated with increased lipid peroxidation (oxidative stress). This may contribute to the accelerated vascular disease associated with these conditions. It is not known whether the coexistence of elevated homocysteine levels will stimulate oxidative stress further than that caused by diabetes alone. Plasma concentrations of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, were measured in patients with NIDDM who had previously had a methionine load test; some of the patients had hyperhomocysteinemia. Plasma TBARS concentrations were elevated in diabetics with vascular disease. The additional presence of hyperhomocysteinemia was not associated with a further increase in plasma TBARS concentrations. Lipid peroxidation is increased in patients with diabetes mellitus and macrovascular disease and is not further elevated by the coexistence of elevated homocysteine levels. It is possible that diabetes maximally stimulates oxidative stress and any further acceleration of vascular disease in patients who have coexistent hyperhomocysteinemia is mediated through mechanisms other than lipid peroxidation.