Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Relationships between skin temperature (Tsk) and perfusion have been studied to provide a basis for the use of Tsk in the non-invasive assessment of limb circulation in peripheral vascular disease. Raising the ambient temperature (Ta) from 20 to 30 degrees C increased the perfusion of the glabrous skin of the hands and feet without changing that of the skin of the forearm or calf. On a fractional basis the response in the hand and foot was the same. Tsk was higher in the arms than the legs and in the proximal than distal parts of the limbs. A fall in Tsk was often seen when Ta rose from 20 to 25 degrees C and was attributed to counter-current cooling. Subsequently Tsk rose even in regions where there was no increase in skin perfusion. Tsk can only be related to its perfusion in the fingers, palm and toes. Forearm Tsk was related to the perfusion of the digits. This relationship implies a link with the arterial inflow to the limb which determines the size of its thermal core. Heat conduction from the core seemed important for the skin of areas like the forearm and calf where the constant, low perfusion limited the amount of heat which could be transported to it directly by the blood. The importance of conduction was supported by studies, at Ta 20 degrees C, on subjects during calf muscle exercise and on patients with arterio-venous fistulae. Here an increase in the arterial inflow to the limb was associated with a rise in Tsk of the forearm/calf unrelated to the perfusion of its skin.
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PMID:Relationships between skin temperature and perfusion in the arm and leg. 201 76

Angiogenesis is implicated in the pathogenesis of cancer, rheumatoid arthritis, and atherosclerosis and in the treatment of coronary artery and peripheral vascular disease. Here, cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are shown to interfere with angiogenesis. In vivo, the HMG-CoA reductase inhibitor simvastatin dose-dependently inhibited capillary growth in both vascular endothelial growth factor-stimulated chick chorioallantoic membranes and basic fibroblast growth factor-stimulated mouse corneas. In vitro, the development of tubelike structures by human microvascular endothelial cells cultured on 3D collagen gels was inhibited at simvastatin concentrations similar to those found in the serum of patients on therapeutic doses of this agent. HMG-CoA reductase inhibitors interfered with angiogenesis via inhibition of the geranylgeranylation and membrane localization of RhoA. Simvastatin inhibited membrane localization of RhoA with a concentration dependence similar to that for the inhibition of tube formation, whereas geranylgeranyl pyrophosphate, the substrate for the geranylgeranylation of Rho, reversed the effect of simvastatin on tube formation and on the membrane localization of RhoA. Furthermore, tube formation was inhibited by GGTI, a specific inhibitor of the geranylgeranylation of Rho; by C3 exotoxin, which inactivates Rho; and by the adenoviral expression of a dominant-negative RhoA mutant. The expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on tube formation. Finally, HMG-CoA reductase inhibitors inhibited signaling by vascular endothelial growth factor, Akt, and focal adhesion kinase, three RhoA-dependent pathways known to be involved in angiogenesis. This study demonstrates a new relationship between lipid metabolism and angiogenesis and an antiangiogenic effect of HMG-CoA reductase inhibitors with possible important therapeutic implications.
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PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. 1214 47

Chronic exposure to arsenic has been linked to tumorigenesis, cardiovascular disease, hypertension, atherosclerosis, and peripheral vascular disease; however, the molecular mechanisms underlying its pathological effects remain elusive. In this study, we investigated arsenic-induced alteration of focal adhesion protein complexes in normal, primary vascular smooth muscle cells. We demonstrate that exposure to environmentally relevant concentrations of arsenic (50 ppb As(3+)) can alter focal adhesion protein co-association leading to activation of downstream pathways. Co-associated proteins were identified and quantitated via co-immunoprecipitation, SDS-PAGE, and Western blot analysis followed by scanning densitometry. Activation of MAPK pathways in total cell lysates was evaluated using phosphor-specific antibodies. In our model, arsenic treatment caused a sustained increase in FAK-src association and activation, and induced the formation of unique signaling complexes (beginning after 3-hour As(3+) exposure and continuing throughout the 12-hour time course studied). The effects of these alterations were manifested as chronic stimulation of downstream PAK, ERK and JNK pathways. Past studies have demonstrated that these pathways are involved in cellular survival, growth, proliferation, and migration in VSMCs.
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PMID:Arsenic alters vascular smooth muscle cell focal adhesion complexes leading to activation of FAK-src mediated pathways. 1848 77

We report two patients with peripheral vascular disease requiring multiple bilateral radiologic and surgical interventions, and whose disease was unresponsive to conventional anticoagulation and antiplatelet therapy. Although thrombocytosis was only intermittent, analysis of the Janus kinase 2 (JAK2) gene revealed a V617F mutation, thus confirming the presence of an underlying occult myeloproliferative disorder. We propose that JAK2 mutation analysis be considered in patients with recurrent, unexplained arterial events to identify those with occult myeloproliferative disorders.
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PMID:Recurrent refractory arterial thromboembolism associated with the Janus kinase 2 V617F mutation. 1917 56

People with diabetes suffer from early accelerated atherosclerosis, which contributes to morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Atherosclerosis is thought to initiate at sites of endothelial cell injury. Hyperglycemia, a hallmark of diabetes, leads to non-enzymatic glycosylation (or glycation) of extracellular matrix proteins. Glycated collagen alters endothelial cell function and could be an important factor in atherosclerotic plaque development. This study examined the effect of collagen glycation on endothelial cell response to fluid shear stress. Porcine aortic endothelial cells were grown on native or glycated collagen and exposed to shear stress using an in vitro parallel plate system. Cells on native collagen elongated and aligned in the flow direction after 24 h of 20 dynes/cm(2) shear stress, as indicated by a 13% decrease in actin fiber angle distribution standard deviation. However, cells on glycated collagen did not align. Shear stress-mediated nitric oxide release by cells on glycated collagen was half that of cells on native collagen, which correlated with decreased endothelial nitric oxide synthase (eNOS) phosphorylation. Glycated collagen likely inhibited cell shear stress response through altered cell-matrix interactions, since glycated collagen attenuated focal adhesion kinase activation with shear stress. When focal adhesion kinase was pharmacologically blocked in cells on native collagen, eNOS phosphorylation with flow was reduced in a manner similar to that of glycated collagen. These detrimental effects of glycated collagen on endothelial cell response to shear stress may be an important contributor to accelerated atherosclerosis in people with diabetes.
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PMID:Glycated collagen alters endothelial cell actin alignment and nitric oxide release in response to fluid shear stress. 2155 27

Chronic kidney disease (CKD) is a significant risk factor for cardiovascular and peripheral vascular disease. Although mesenchymal stem cell (MSC)-based therapy is a promising strategy for treatment of ischemic diseases associated with CKD, the associated pathophysiological conditions lead to low survival and proliferation of transplanted MSCs. To address these limitations, we investigated the effects of fucoidan, a sulfated polysaccharide, on the bioactivity of adipose tissue-derived MSCs and the potential of fucoidan-treated MSCs to improve neovascularization in ischemic tissues of CKD mice. Treatment of MSCs with fucoidan increased their proliferative potential and the expression of cell cycle-associated proteins, such as cyclin E, cyclin dependent kinase (CDK) 2, cyclin D1, and CDK4, via focal adhesion kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt axis. Moreover, fucoidan enhanced the immunomodulatory activity of MSCs through the ERK-IDO-1 signal cascade. Fucoidan was found to augment the proliferation, incorporation, and endothelial differentiation of transplanted MSCs at ischemic sites in CKD mice hind limbs. In addition, transplantation of fucoidan-treated MSCs enhanced the ratio of blood flow and limb salvage in CKD mice with hind limb ischemia. To our knowledge, our findings are the first to reveal that fucoidan enhances the bioactivity of MSCs and improves their neovascularization in ischemic injured tissues of CKD. In conclusion, fucoidan-treated MSCs may provide an important pathway toward therapeutic neovascularization in patients with CKD.
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PMID:Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease. 2721 70