Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human serum paraoxonase (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidation of low-density lipoprotein (LDL) in vitro, suggesting that PON1 protects against atherosclerosis. We detected 3 polymorphisms of the PON1 gene and investigated PON1 enzyme activities as paraoxonase (PON), arylesterase (ARYL) and diazoxonase (DIAZ), and serum PON1 concentration in 106 patients with type 2 diabetes and 161 control subjects. All 3 enzyme activities and specific activities of PON1 in diabetic patients were significantly lower than those in controls, while there was no difference in serum PON1 concentration between the patient and control groups. The specific activities of PON, ARYL, and DIAZ in patients were 6.82 +/- 3.14 nmol x min(-1) x U(-1) (mean +/- SD, U; unit for serum PON1 concentration), 4.77 +/- 0.17 micromol x min(-1) x U(-1), and 193 +/- 92 nmol x min(-1) x U(-1), respectively, whereas those in controls were 9.33 +/- 3.92 nmol x min(-1) x U(-1), 5.36 +/- 0.14 micromol x min(-1) x U(-1), and 242 +/- 103 nmol x min(-1) x U(-1), respectively. There was no significant difference in the allelic frequencies of -108C/T, 55L/M, or 192Q/R between the patient and control groups. When each enzyme activity was compared between the patient and control groups in each genotype subgroup, all activities were lower in the patient group. The PON and ARYL activities were lower in patients with retinopathy or nephropathy than in those without such complications, and the ARYL activity was also lower in patients with neuropathy. In conclusion, all specific enzyme activities of PON1 were lower in patients with type 2 diabetes independent of the -108C/T, 55L/M, or 192Q/R polymorphism, and this impaired PON1 function may be involved in development of diabetic microangiopathy.
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PMID:Serum arylesterase/diazoxonase activity and genetic polymorphisms in patients with type 2 diabetes. 1109 1

Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.
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PMID:Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. 1113 24

The aim of our study was to investigate the effects of Pycnogenol on the progression of diabetic retinopathy and other vascular retinal disorders. The study consisted of a double-blind phase in which 20 patients were recruited and randomly treated with placebo or Pycnogenol (50 mg x 3/day for 2 months) and an open phase in which another 20 patients were treated with Pycnogenol at the same dose schedule. In total, 40 patients with diabetes, atherosclerosis and other vascular diseases involving the retina were enrolled; 30 of them were treated with Pycnogenol and 10 with placebo. The results demonstrated a beneficial effect of Pycnogenol on the progression of retinopathy. Without any treatment (placebo) the retinopathy progressively worsened during the trial and the visual acuity significantly decreased; on the contrary, the Pycnogenol-treated patients showed no deterioration of retinal function and a significant recovery of visual acuity was also obtained. The fluorangiography showed an improvement of retinal vascularization and a reduced endothelial permeability and leakage in the Pycnogenol, but not in the placebo-treated, patients. The ophthalmoscopy and the electroretinogram (ERG) also confirmed the beneficial effects of Pycnogenol. The mechanism of action of Pycnogenol may be related to its free radical (FR) scavenging, anti-inflammatory and capillary protective activities. It has been suggested that Pycnogenol may bind to the blood vessel wall proteins and mucopolysaccharides and produce a capillary 'sealing' effect, leading to a reduced capillary permeability and oedema formation.
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PMID:Treatment of vascular retinopathies with Pycnogenol. 1135 56

Cardiovascular and renal diseases in diabetes stem from an accelerated form of atherosclerosis in both small and large blood vessels. Diabetic nephropathy is a clinical hallmark of microangiopathy and often leads to end-stage renal failure. Significantly, microalbuminuria is an independent predictor of cardiovascular morbidity and mortality in both the diabetic and non-diabetic population. In diabetic patients, it is also strongly associated with proliferative retinopathy, neuropathy and hypertension. Effective blood pressure reduction in patients with type 2 diabetes and diabetic nephropathy is known to reduce albuminuria, delay the progression of diabetic nephropathy, postpone renal failure and improve survival. These benefits have been demonstrated with a variety of blood pressure-lowering agents, including beta-blockers, calcium channel blockers, diuretics and angiotensin-converting enzyme (ACE) inhibitors. Less is known about the renal effects of the newest class of antihypertensive agents, the angiotensin II receptor antagonists (AIIRAs). Irbesartan is an AIIRA that provides antihypertensive efficacy comparable to ACE inhibitors but with superior tolerability. The PRogram for Irbesartan Mortality and morbidity Evaluations (PRIME) is an important morbidity and mortality program encompassing the Irbesartan Diabetic Nephropathy Trial (IDNT) and the IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients (IRMA II) study. PRIME is evaluating the effects of irbesartan in preventing diabetic nephropathy and end-stage renal failure and in reducing cardiovascular events in high-risk hypertensive patients with type 2 diabetes. The trials were completed at the end of 2000.
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PMID:Hypertension and diabetes: the scope of the problem. 1146 14

Retinal microvascular abnormalities, such as generalized and focal arteriolar narrowing, arteriovenous nicking and retinopathy, reflect cumulative vascular damage from hypertension, aging, and other processes. Epidemiological studies indicate that these abnormalities can be observed in 2-15% of the nondiabetic general population and are strongly and consistently associated with elevated blood pressure. Generalized arteriolar narrowing and arteriovenous nicking also appear to be irreversible long-term markers of hypertension, related not only to current but past blood pressure levels as well. There are data supporting an association between retinal microvascular abnormalities and stroke, but there is no convincing evidence of an independent or direct association with atherosclerosis, ischemic heart disease, or cardiovascular mortality. New computer-related imaging methods are currently being developed to detect the presence and severity of retinal arteriolar narrowing and other microvascular characteristics. When reliably quantified, retinal microvascular abnormalities may be useful as risk indicators for cerebrovascular diseases.
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PMID:Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. 1152 92

Clinical trials of cardiovascular gene therapy, whether using viral (53%) or nonviral (47%) vectors, have thus far disclosed no evidence indicative of inflammatory or other complications, including death, directly attributable to the vector used. Indeed, despite the fact that initial trials of cardiovascular gene therapy targeted patients with end-stage vascular disease, including critical limb ischemia and refractory myocardial ischemia, the mortality for patients enrolled in clinical trials of cardiovascular gene therapy reported to date compares favorably with mortality for similar groups of patients in contemporary controlled studies of medical or interventional therapies. The most common morbidity reported after cardiovascular gene transfer is lower extremity edema; in contrast to data involving genetically engineered mice, however, evidence of life- or limb-threatening edema has not been described in any patients, including patients after gene transfer for myocardial ischemia. Concerns regarding the potential for angiogenic cytokines to promote the progression of atherosclerosis are not supported by angiographic follow-up of patients with coronary or peripheral vascular disease. The levels and duration of gene expression investigated for therapeutic angiogenesis transfer have been unassociated with hemangioma formation. Likewise, there is little evidence from either preclinical or clinical studies to support the notion that the administration of angiogenic growth factors, per se, is sufficient to stimulate the growth of neoplasms. Patients enrolled in clinical studies of angiogenic cytokines, including patients with diabetes and a previous history of retinopathy, have disclosed no evidence to suggest that ocular pathology is a risk of angiogenic growth factor gene transfer.
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PMID:Assessment of risks associated with cardiovascular gene therapy in human subjects. 1153 99

The ubiquitously found beta-amino acid taurine has several physiological functions, e.g. in bile acid formation, as an osmolyte by cell volume regulation, in the heart, in the retina, in the formation of N-chlorotaurine by reaction with hypochlorous acid in leucocytes, and possibly for intracellular scavenging of carbonyl groups. Some animals, such as the cat and the C57BL/6 mouse, have disturbances in taurine homeostasis. The C57BL/6 mouse strain is widely used in diabetic and atherosclerotic animal models. In diabetes, the high extracellular levels of glucose disturb the cellular osmoregulation and sorbitol is formed intracellularly due to the intracellular polyol pathway, which is suspected to be one of the key processes in the development of diabetic late complications and associated cellular dysfunctions. Intracellular accumulation of sorbitol is most likely to cause depletion of other intracellular compounds including osmolytes such as myo-inositol and taurine. When considering the clinical complications in diabetes, several links can be established between altered taurine metabolism and the development of cellular dysfunctions in diabetes which cause the clinical complications observed in diabetes, e.g. retinopathy, neuropathy, nephropathy, cardiomyopathy, platelet aggregation, endothelial dysfunction and atherosclerosis. Possible therapeutic perspectives could be a supplementation with taurine and other osmolytes and low-molecular compounds, perhaps in a combinational therapy with aldose reductase inhibitors.
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PMID:The role of taurine in diabetes and the development of diabetic complications. 1174 39

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since plasma endothelin concentrations were released from vascular endothelial cells, we have investigated the possible relationship between endothelin 1 (ET-1) and arterial wall thickness. Ninety-eight patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 50 non-diabetic subjects were studied. After an overnight fast, blood was taken for ET-1, glucose, HbA1c, lipids, insulin and C-peptide. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by B-mode ultrasound. ET-1 levels were significantly elevated in diabetic patients with IMT>1100 microm, 8.3 pmol/l (5.2-12.9) compared with control subjects, 7.6 pmol/l (5.0-11.0), p<0.01 and with diabetic subjects with IMT<500 microm, 7.43 pmol/l (4.8-11.1), p<0.01. The diabetic (IMT>1100 microm) study group had also significantly higher levels of insulin, 102.8 +/- 46.4 pmol/l vs control subjects, 77.5 +/- 32.4 pmol/l, p<0.01. In diabetic subjects, no correlation was found between ET-1 and IMT with glucose, HbA1c, lipids, age or duration of diabetes, respectively. We conclude that ET-1 levels are elevated in Type 2 diabetic patients with increased IMT. Thus providing further support for the role of endothelin in atherosclerosis.
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PMID:Plasma levels of endothelin and early carotid atherosclerosis in diabetic patients. 1175 70

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since vascular endothelium is the site of formation of several substances, we have investigated the rate of progression of carotid atherosclerosis and the contribution of endothelin (ET-1), lipid peroxides [measured as thiobarbituric acid reacting species (TBARS)] and 6-keto-Prostaglandin-F1A (6-keto-PG-F1A) at baseline and after 30-months. Fifty patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 27 healthy, non-diabetic persons were studied. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by b-mode ultrasound. The IMT values was significantly increased in diabetic subjects (at baseline: 1110 +/- 310 microm, after 30 months: 1260 +/- 280 microm, p < 0.01), but not in control subjects (1100 +/- 280 microm, 1200 +/- 290 microm, respectively). At baseline time both groups had similar levels of ET-1, TBARS and 6-keto-PG-F1A. In 30-months follow-up, the ET-1 level 8.0 pmol/l (5.8-10.7) was significantly elevated in diabetic subjects, compared with the level at baseline time 7.43 pmol/l (4.8-11.1) p < 0.01. No significant differences were found in the other examined parameters in the studied groups. Although insulin levels remained unchanged in the two studied groups, in 30 months follow-up, the insulin level in the diabetic subjects, 92.4 +/- 35.1 pmol/l was significantly elevated compared with those of control subjects 76.0 +/- 31.0 pmol/l, p < 0.05. In conclusion, endothelis is the main associate of the change of IMT value over 30 months in diabetic patients, in whom the extent of atherosclerosis was significantly greater than in control subjects.
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PMID:Progression of carotid atherosclerosis and the role of endothelin in diabetic patients. 1175 71

Chronic hyperglycaemia contributes to tissue and organ damage retina, kidney and nerves by promoting the formation of advanced glycosylation end products (AGE). The AGE accumulation both in intra and extracellular proteins plays an essential role in the pathogenesis of diabetic complications by production of cross links on extracellular matrix proteins, by interaction with specific cellular receptors and by modification of nucleic acids. Human studies are being conducted to examine the pharmacokinetics efficacy and toxicity of pharmacologic agents that inhibit the AGE formation--aminoguanidine and aminoguandine-like--in order to define its role in the prevention and treatment of retinopathy, nephrology, neuropathy and diabetic atherosclerosis.
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PMID:[Advanced glycosylation in diabetes mellitus. Occurrence of late complications]. 1176 82


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