Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin resistance syndrome (IRS) with obesity is large-word wide-spread and represents a strong risk factor for vascular disease. Atherothrombotic complications in IRS are partly attributed to a dysregulation of hemostasis inducing a prothrombotic state which includes endothelial activation, hyperactivity of platelets, hypercoagulability and hypofibrinolysis. This latter, due to elevated PAI-1 levels, is a core feature of the IRS. Most of the prothrombotic modifications can be reversed by loosing weight. Low grade inflammation with prolonged cytokines mediated acute phase reaction is actually considered as strongly related to the IRS and is involved in the dysregulation of hemostasis. TNF pathway and TGFb play an important role in the regulation of PAI-1 synthesis in the adipose tissue and the liver with steatosis. Interestingly, modulation of PAI-1 expression in adipose tissue influences adipose tissue growth, increasing once more the spectrum of the non hemostatic functions of coagulation/fibrinolysis parameters.
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PMID:The insulin resistance syndrome: implications for thrombosis and cardiovascular disease. 1367 55

Type 2 diabetes is characterised by insulin resistance in association with clustering of atherothrombotic risk factors (dysglycaemia, hyperinsulinaemia, hypertension, raised triglyceride, low HDL cholesterol and increased levels of plasminogen activator inhibitor-1 (PAI-1) and clotting factor VII). There is a 3-5 fold increase in risk of myocardial infarction rising to 10-20 fold in the presence of microalbuminuria and overall around 70-75% of subjects with type 2 diabetes die of cardiovascular disease. However, classical risk factors which associate with insulin resistance do not account for all the increased burden of vascular disease in diabetic subjects. Metformin is a biguanide compound which is antihyperglycaemic, reduces insulin resistance and has cardioprotective effects on lipids, thrombosis and blood flow. Metformin has a weight neutral/weight lowering effect and reduces hypertriglyceridaemia, elevated levels of PAI-1, factor VII and C-reactive protein. In addition recent studies indicate that metformin has direct effects on fibrin structure/function and stabilises platelets, two important components of arterial thrombus. The United Kingdom Prospective Diabetes Study (UKPDS) reported that metformin was associated with a 32% reduction in any diabetes related endpoint (p<0.002), a 39% reduction in myocardial infarction (p<0.01) and a non-significant 29% fall in microvascular complications. The figures for macrovascular complications compare favourably for those described for other cardioprotective agents such as ACE inhibitors and statins. These findings confirm metformin as first line therapy in the management of obese insulin resistant type 2 diabetes and in the prevention of the vascular complications of this common condition.
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PMID:Beneficial effects of metformin on haemostasis and vascular function in man. 1450

A 74-year-old woman had a history over 25 years of endarterectomy of both renal arteries, iliac venous thrombosis, pulmonary embolism, left internal carotid artery endarterectomy, coronary angioplasty, aortocoronary bypass grafting, occlusion of the right axillary artery, lower-limb claudication due to common iliac artery aneurysm, external iliac artery stenosis, multiple femoral artery stenoses, bifurcational stent grafting, occlusion of the left brachial artery and the right external iliac artery, and stroke. Assessment of the risk-factor profile revealed an absence of classic risk factors but the presence of the factor V Leiden mutation, the methylenetetrahydrofolate reductase AI298C mutation, the HFE C282Y mutation, plasminogen activator inhibitor-1 gene mutation, the -455 G/A fibrinogen gene polymorphism, the epsilon3/epsilon4 apolipoprotein E -675 4G gene polymorphism, and hyperhomocysteinemia. This case shows that severe, generalized, occlusive vascular disease may be due to the combination of various genetic risk factors for atherosclerosis and venous thromboembolism.
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PMID:Risk-factor profile in severe, generalized, obliterating vascular disease. 1474 32

Complex inter-relationships between age-associated illnesses, such as vascular disease and Alzheimer's disease (AD), suggest that biological and genetic pathways may be worthy of examination in centenarian populations to provide insights into human longevity. This is also borne out by the involvement of lipoprotein metabolism and a number of vascular genetic risk factors. Repeated findings of a higher frequency of the apolipoprotein E (APOE) epsilon4 allele in middle-aged subjects compared with centenarians were reported. Furthermore, we have also shown how in different populations there is a significant trend in reduction of serum APOE levels from APOE epsilon2- to epsilon4-carrier as well as significant differences in serum APOE levels respect to age in epsilon4-carriers but only after adjustment for HDL cholesterol. In contrast, findings of increased prevalence of the angiotensin I converting enzyme 1 (ACE1) D allele in French centenarians have not been replicated, suggesting the possibility that regional differences may occur in ACE1(*)D frequency within Europe in centenarians, as has been recently reported for APOE epsilon2 and epsilon4 alleles. A number of studies have examined the potential role in longevity of other genes involved in vascular risk, haemostasis, and blood pressure regulation [methyltetrahydrofolatereductase (MTHFR), apolipoprotein A1 (APOA-I), apolipoprotein C3 (APOC-III), apolipoprotein A4 (APOA-IV), paraoxonase 1 (PON1), plasminogen activator inhibitor type I (PAI-1)], with contrasting results. While further studies are needed to confirm the possible role of APOE concentration as putative longevity factor, this paper provides an overview of genetic vascular factors potentially involved in human longevity.
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PMID:Vascular genetic factors and human longevity. 1501 61

Adipose tissue plays an active role in energy balance because it is not only a lipid storing and mobilizing tissue but consists of functionally specialized tissues able to produce heat (in brown adipose tissue) and to produce or release a vast number of so called adipokines or adipocytokines. These consist of polypeptides but also non-protein factors and are metabolically active molecules belonging to different functional categories like immunity (complement factors, haptoglobin), endocrine function (leptin, sex steroids, various growth factors), metabolic function (fatty acids, adiponectin, resistin), and cardiovascular function (angiotensinogen, PAI-1). Recent advances using genomic and proteomic approaches have identified numerous new adipocyte secreted factors whose function remain to be established. Too little as well as too much adipose tissue leads to metabolic disturbances like insulin resistance. Visceral obesity is especially strongly correlated with the development of diabetes, hypertension and cardio-vascular disease. Thermogenesis in brown adipose tissue is a means to dissipate excess energy, but in adult humans brown fat is very scarce and probably not functional. However, human white adipose tissue contains mesenchymal stem cells, and if these could be stimulated to differentiate into brown adipocytes, increased energy expenditure in white fat could help to shift energy balance towards a more negative state.
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PMID:Adipose tissue as a regulator of energy balance. 1505 10

Fibrinolysis plays a crucial role in the development of vascular disease. The interface between the plasminogen activators and inhibitors determines the fibrinolytic potential of human blood. In addition to fibrin degradation, fibrinolytic system components modulate several complex biological events such as angiogenesis, tumorigenesis, arteriosclerosis and cellular migration. Recent experimental and clinical data indicated that PAI-1 as a novel vascular risk factor. In this concise review, we will examine the accumulating evidence suggesting that there is an intricate relationship between these systems which may provide new therapeutic strategies for prevention of vascular disease.
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PMID:Pivotal role of plasminogen-activator inhibitor 1 in vascular disease. 1570 73

During the past decade, our understanding of the pathophysiology of coronary heart disease (CAD) has undergone a remarkable evolution. To date atherosclerosis is considered an inflammatory disease, whose the endothelial dysfunction represents an early key event. When the arterial endothelium encounters certain bacterial products or risk factors, such as dyslipidemia, vasoconstrictor hormones involved in hypertension, the products of glycoxidation associated with hyperglycemia, or proinflammatory cytokines derived from excess adipose tissue, these cells increase the expression of adhesion molecules that promote the sticking of blood leukocytes to the inner surface of the arterial wall. Once in the arterial intima these cells communicate with endothelium and smooth muscle cells, under the influence of mediators of inflammation and immunity, such as the cytokines and complements components, prostanoids and leukotrienes. Thus, the activated endothelium promotes the development of the atherosclerotic disease process, i.e., vascular inflammation and thrombosis by producing vasoconstrictor substances, by inducing the expression of adhesive receptors for leukocytes and platelets, the production of tissue factor and endothelin, and by increasing the production of the plasminogen activator inhibitor-1. Emerging data support the concept that assessment of endothelial vasomotion may be a useful biomarker for atherosclerotic vascular disease.
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PMID:Endothelium and inflammation. 1621 Sep 92

Review of literature has shown an increased rate of thrombotic complications in diabetic patients with frequent episodes of hyperketonemia. However, the mechanisms by which ketosis promotes vascular disease in diabetic patients are unclear. It was the aim of this study to investigate early changes in haemostatic parameters and oxidative stress markers during the hyperketonemic status which follows the interruption of continuous subcutaneous insulin infusion (CSII) in type I diabetic patients. Eight CSII-treated type I diabetic patients underwent a 4-hour pump arrest. Blood glucose, insulin and 3-hydroxybutirate were measured to verify the metabolic response. A vein-occlusive (VO) test was performed for the determination of tPA and PAI-1 activities and their antigen levels before and after the CSII arrest. Coagulation factor VII and VIII were evaluated by one-stage PT and PTT method, respectively. TF, vWF, tPA and PAI-1 antigens were determined by ELISA, whereas tPA and PAI-1 activities using chromogenic methods. Plasma malondialdehyde (MDA) and protein carbonyl groups (PCG) levels were determined by HPLC and spectrophotometry, respectively. After the insulin deprivation phase, post-VO tPA antigen level significantly decreased (P = 0.0391), whereas TF and post-VO PAI-1 activity and antigen levels significantly increased (P = 0.0156 and P = 0.0234, respectively). Plasma MDA and PCG levels were 1.88-fold and 1.74-fold higher than baseline values, respectively. In conclusion, the impairment of the fibrinolytic potential and the increases in TF, MDA and PCG levels may enhance the risk of both arterial and venous thrombosis during ketosis. Thus, early detection of hyperketonemia in DM patients could contribute to the prevention of life-threatening vascular events.
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PMID:Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type 1 diabetic patients. 1784 53

Thrombotic complications of vascular disease constitute the leading cause of morbidity and mortality in much of the developed world. Current drug therapies available to treat the thrombotic component of arterial and venous vascular complications remain limited. Novel safe and effective treatment strategies to reduce formation of occlusive thrombosis will likely have a major impact on reducing the economic burden of vascular disease on the healthcare system. Enhancing endogenous fibrinolysis by targeting plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of circulating plasminogen activators, has been shown to be effective in markedly attenuating the formation of arterial and venous occlusive thrombosis in animal models. In addition, animal and human studies of PAI-1 deficiency indicate that spontaneous bleeding complications associated with even complete PAI-1 deficiency would be rare. Patients most likely to benefit from PAI-1 inhibition would be those at high risk for vascular events where PAI-1 is elevated, such as is observed in obesity, diabetes and the metabolic syndrome. Since obesity and metabolic syndrome are now epidemic, and will likely have a major adverse impact on vascular thrombotic events, it may be time to test the clinical effectiveness of PAI-1 inhibition in a patient population at high risk for vascular thrombosis.
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PMID:Plasminogen activator inhibitor-1 in vascular thrombosis. 1789 48

Recent studies suggest that adipocyte-secreted factors called adipokines are involved in obesity-associated complications including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Among those, adiponectin is an antidiabetic and antiatherogenic protein, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. In contrast, leptin, tumor necrosis factor a, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 are upregulated in obesity and contribute to the development of diabetes and vascular disease. In this review, the relevance of adipokines in obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular diseases is discussed.
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PMID:Adipokines in diabetes and cardiovascular diseases. 1791 55


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