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)

Five types of oral antihyperglycemic drugs are currently approved for the treatment of diabetes: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. We briefly review the cardiovascular effects of the most commonly used antidiabetic drugs in these groups in an attempt to improve knowledge and awareness regarding their influences and potential risks when treating patients with coronary artery disease (CAD). Regarding biguanides, gastrointestinal disturbances such as diarrhea are frequent, and the intestinal absorption of group B vitamins and folate is impaired during chronic therapy. This deficiency may lead to increased plasma homocysteine levels which, in turn, accelerate the progression of vascular disease due to adverse effects on platelets, clotting factors, and endothelium. The existence of a graded association between homocysteine levels and overall mortality in patients with CAD is well established. In addition, metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as heart failure or recent myocardial infarction. Sulfonylureas avoid ischemic preconditioning. During myocardial ischemia, they may prevent opening of the ATP-dependent potassium channels, impeding the necessary hyperpolarization that protects the cell by blocking calcium influx. Meglitinides may exert similar effects due to their analogous mechanism of action. During treatment with glitazones, edema has been reported in 5% of patients, and these drugs are contraindicated in diabetics with NYHA class III or IV cardiac status. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates and on diabetic micro- and macrovascular complications is still unknown. Combined sulfonylurea/metformin therapy reveals additive effects on mortality. Four points should be mentioned: (1) the five oral antidiabetic drug groups present proven or potential cardiac hazards; (2) these hazards are not mere 'side effects' but are deeply rooted in the drugs' mechanisms of action; (3) current data indicate that combined glibenclamide/metformin therapy seems to present a special risk and should be avoided in the long-term management of type 2 diabetics with proven CAD, and (4) Non-Insulin Antidiabetic Therapy in Diabetic Cardiac Patients 155 customized antihyperglycemic pharmacological approaches should be investigated for the optimal treatment of diabetic patients with heart disease. New possibilities are represented by incretin mimetic compounds, dipeptidyl peptidase (DPP)-4 inhibitors, inhaled insulin and eventually oral insulin.
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PMID:Non-insulin antidiabetic therapy in cardiac patients: current problems and future prospects. 1823 Sep 61

A large body of evidence indicates that sporadic Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and needs to be treated and managed as such. Epidemiologic studies of vascular risk factors, together with preclinical detection tools for AD are proof of concept that cerebral hypoperfusion is one of the earliest pathological signs in the development of cognitive failure. Vascular risk factors involving heart disease and stroke in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to further decline in cerebral blood flow (CBF) resulting in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, can reach a critically attained threshold of cerebral hypoperfusion (CATCH) giving rise to a neuronal energy crisis via reduced ATP synthesis. The ensuing metabolic energy crisis initially carves up ischemic-sensitive neurons in the hippocampus and posterior parietal cortex setting up cognitive meltdown and progressive neurodegenerative and atrophic changes in the brain. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic membrane pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid precursor protein resulting in beta-amyloid deposition and axonal microtubule disruption from tau hyperphosphorylation. The high energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques can predict AD preclinically at the mild cognitive impairment stage or even before any clinical manifestation of dementia is expressed. Clinical diagnostic assessment of elderly persons who could develop or already present with memory complaints can prevent, reverse or slow down AD development. Although pathologic aging is the subject of thousands of studies, the question of why the elderly (and not younger people) succumb to AD has not been adequately addressed. The explanation(s) as to why vascular risk factors, for example, can trigger AD or vascular dementia usually in the elderly and not the young should provide vital clues in the search for a strategically effective dementia treatment. This review offers inductive hypothetical darts relative to that critical question.
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PMID:Pathophysiology of neuronal energy crisis in Alzheimer's disease. 1832 69

Metabolic syndrome is characterized by increased cardiovascular risk. Pentraxin 3 (PTX3), an acute phase protein, is involved in atherosclerosis. No information is available on PTX3 plasma concentrations in metabolic syndrome and on its associations with metabolic alterations and subclinical atherosclerosis. The aim of this study was to assess PTX3 plasma levels in metabolic syndrome patients compared to control subjects and their potential associations with anthropometric and clinical components of the syndrome as well as with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis. Plasma was obtained from metabolic syndrome patients (NCEP-ATP III criteria n = 41, 20 M/21F) and by age-matched control subjects (n = 32, 16 M/16F). PTX3 was measured using sandwich ELISA and cIMT with ultrasound. Compared to those of the control subjects, plasma levels of PTX3 were higher (? * 100%, P = 0.0009) in metabolic syndrome patients. In univariate analysis, plasma PTX3 was negatively (P = 0.005) associated with high-density lipoprotein (HDL) cholesterol and positively (P = 0.046) with plasma triglycerides and with cIMT (P = 0.045) in the patients (n = 41). In multivariate analysis the direct association between PTX3 and cIMT was no longer significant after correction for HDL. None of these associations were detected in the control patients. These data demonstrate that PTX3, a novel marker of vascular disease, is higher in patients with metabolic syndrome associated with subclinical atherosclerosis. In addition, PTX3 is significantly independently correlated with low HDL cholesterol, but not with cIMT, suggesting a novel association between PTX3 and atherogenic lipid profile.
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PMID:Circulating pentraxin 3 levels are higher in metabolic syndrome with subclinical atherosclerosis: evidence for association with atherogenic lipid profile. 1923 13

Beta-amyloid (Abeta) deposition, in the form of plaques and amyloid angiopathy, and hyper-phosphorylated tau deposition forming neurofibrillary tangles, dystrophic neurites around beta-amyloid plaques and neuropil threads, are neuropathological hallmarks of Alzheimer's disease (AD) that accumulate in the brain with disease progression. These changes are accompanied by progressive loss of synapses and nerve cell death. Progressive cognitive impairment and dementia are the main neurological deficits. In addition, there is cumulative evidence demonstrating other metabolic disturbances that impair cell function and hamper neuron viability. The main components of the mitochondria are altered: complex IV of the respiratory chain is reduced; complex V which metabolizes ADP to form ATP is oxidatively damaged and functionally altered; and voltage-dependent anion channel VDAC, a major component of the outer mitochondrial membrane that regulates ion fluxes, is damaged as a result of oxidative stress. Mitochondria are a major source of reactive oxygen species that promote oxidative damage to DNA, RNA, proteins and lipids. Protein targets of oxidative damage are, among others, several enzymatic components of the glycolysis, lipid metabolism and cycle of the citric acid that fuel oxidative phosphorylation, mitochondrial respiration and energy production. The lipid composition of lipid rafts, key membrane specializations that facilitate the transfer of substrates, and protein-protein and lipid-protein interactions, is altered as a result of the abnormally low levels of n-3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid) that increase viscosity and augment energy consumption. Abnormal lipid raft composition may also modify the activity of key enzymes that modulate the cleavage of the amyloid precursor protein to form toxic Abeta. This is further complicated by the disruption of the complex VDAC with estrogen receptor alpha at the caveolae which participates, under physiological conditions, in the protection against beta-amyloid. Together, all these alterations converge in reduced energy production and increased energy demands in altered cells. Cell exhaustion is suggested as being a determining element to interpret impaired neuron function, reduced molecular turnover, and enhanced cell death.
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PMID:Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer's disease. 1979 58

Hyperglycemia is a major risk factor for endothelial dysfunction and vascular disease, and in the current study, the link to glucose-induced abnormal intracellular Ca(2+) (Ca(i)(2+)) homeostasis was explored in bovine aortic endothelial cells in high glucose (HG; 25 mmol/l) versus low glucose (LG; 5.5 mmol/l; control). Transient receptor potential 1 (TRPC1) ion channel protein, but not TRPC3, TRPC4, or TRPC6 expression, was significantly increased in HG versus LG at 72 h. HG for 4, 24, and 72 h did not change basal Ca(i)(2+) or ATP-induced Ca(i)(2+) release; however, the amplitude of sustained Ca(i)(2+) was significantly increased at 24 and 72 h and reduced by low concentration of the putative, but nonspecific, TRPC blockers, gadolinium, SKF-96365, and 2-aminoethoxydiphenyl borate. Treatment with TRPC1 antisense significantly reduced TRPC1 protein expression and ATP-induced Ca(2+) entry in bovine aortic endothelial cells. Although the link between HG-induced changes in TRPC1 expression, enhanced Ca(2+) entry, and endothelial dysfunction require further study, the current data are suggestive that targeting these pathways may reduce the impact of HG on endothelial function.
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PMID:Glucose enhances expression of TRPC1 and calcium entry in endothelial cells. 1985 58

AMP-activated protein kinase (AMPK) was initially viewed as energy sensor and activated by increased intracellular concentrations of AMP following nutrient deprivation. Physiological or pathological stimuli that deplete cellular energy activate AMPK that coordinates a cellular program that limits further ATP depletion and promotes compensatory changes that maintain cellular ATP levels. Recent studies revealed novel roles of AMPK independent of energy status, thereby increasing our understanding of multi-functional roles of AMPK in cells important in pathogenesis of cardiovascular diseases. This enzyme represents an attractive therapeutic target for vascular disease treatment in the future.
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PMID:AMP-activated protein kinase: a stress-responsive kinase with implications for cardiovascular disease. 2006 Jul 80

Depression is associated with vascular disease, such as myocardial infarction and stroke. Pharmacological treatments may contribute to this association. On the other hand, Mg(2+) deficiency is also known to be a risk factor for the same category of diseases. In the present study, we examined the effect of imipramine on Mg(2+) homeostasis in vascular smooth muscle, especially via melastatin-type transient receptor potential (TRPM)-like Mg(2+) -permeable channels. The intracellular free Mg(2+) concentration ([Mg(2+) ](i) ) was measured using (31) P-nuclear magnetic resonance (NMR) in porcine carotid arteries that express both TRPM6 and TRPM7, the latter being predominant. pH(i) and intracellular phosphorus compounds were simultaneously monitored. To rule out Na(+) -dependent Mg(2+) transport, and to facilitate the activity of Mg(2+) -permeable channels, experiments were carried out in the absence of Na(+) and Ca(2+) . Changing the extracellular Mg(2+) concentration to 0 and 6 mM significantly decreased and increased [Mg(2+) ](i) , respectively, in a time-dependent manner. Imipramine statistically significantly attenuated both of the bi-directional [Mg(2+) ](i) changes under the Na(+) - and Ca(2+) -free conditions. This inhibitory effect was comparable in influx, and much more potent in efflux to that of 2-aminoethoxydiphenyl borate, a well-known blocker of TRPM7, a channel that plays a major role in cellular Mg(2+) homeostasis. Neither [ATP](i) nor pH(i) correlated with changes in [Mg(2+) ](i) . The results indicate that imipramine suppresses Mg(2+) -permeable channels presumably through a direct effect on the channel domain. This inhibitory effect appears to contribute, at least partially, to the link between antidepressants and the risk of vascular diseases.
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PMID:Imipramine inhibition of TRPM-like plasmalemmal Mg2+ transport in vascular smooth muscle cells. 2013 12

Vascular disease has importance in chronic diabetes mellitus but long-term impact of maternal diabetes (MD) on vascular function in the offspring is poorly investigated. This study aimed to examine the alterations produced by MD in K (+) channels activity on endothelium-dependent aortic relaxation induced by acetylcholine (ACh) in adult offspring rats. Diabetes mellitus was induced in female Wistar rats by streptozotocin (STZ; 42 mg/kg, i. p.) injected on the 7 (th) day of pregnancy. Body weights of offspring rats from diabetic mothers (O-DR) were significantly lesser than those of offspring rats from control mothers (O-CR). At 120 days of age, triglyceride but not glucose and cholesterol level was significantly higher in O-DR than in O-CR. In aortic preparations from O-DR, norepinephrine (NE)-induced contractions were significantly higher than those observed in O-CR. In aortic preparations from O-DR precontracted with NE (1 muM), vasorelaxant response to either ACh (0.1, 1 and 10 muM) or sodium nitroprusside (0.1, 1 and 10 nM) was significantly reduced when compared to O-CR. In both groups, vasorelaxant responses to ACh were reduced in the presence of tetraethylamonium chloride and 4-aminopyridine. However, pretreatment with glybenclamide reduced vasorelaxant effects of lowest concentration (0.1 muM) of ACh only in preparations from O-CR. Our results suggest a reduced K (+)(ATP) activity in the cholinergic relaxation of aortic rings of adult offspring born to STZ-diabetic mothers.
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PMID:Effects of K+channels inhibitors on the cholinergic relaxation of the isolated aorta of adult offspring rats exposed to maternal diabetes. 2039 25

Ectonucleotidases and the nucleotide metabolism have been implicated as important regulators of various tissue functions in diabetes disease. Here we evaluated the ectonucleotidase activities and the profile of extracellular ATP metabolism in blood serum of streptozotocin (STZ)-induced diabetic rats. We observed a raise in ATP, ADP, AMP, and 5'-TMP hydrolysis in blood serum after 30 days of diabetes induction, when compared with the citrate group. However, in serum of rats treated 6 days with insulin, the hydrolysis returned to the control levels. Extracellular ATP metabolism estimated by HPLC analysis showed a rapid hydrolysis of extracellular ATP by diabetic animals, leading to the formation of high levels of adenosine when compared with citrate and insulin groups. Since in diabetes the vascular disease is frequently present, the alterations observed are important, because these enzymes control the nucleotides/nucleosides ratio in the circulation and thus the events related to haemostasis.
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PMID:The nucleotide hydrolysis is altered in blood serum of streptozotocin-induced diabetic rats. 2042 Apr 81

Vascular disease is a major cause of morbidity and mortality among transplanted recipients and cyclosporine (CsA) treatment has been consistently implicated in this event. In this study we assessed total blood homocysteine levels (tHcy), ecto-nucleotidase activities and adenine nucleotide/nucleoside levels searching for parameters related to the mechanisms of vascular damage induced by chronic CsA treatment in non-transplanted rats. Thirty male Wistar rats were divided in three groups: control group treated with corn oil, CsA 5mg/kg and CsA 15 mg/kg, administered by daily gastric gavage during 8 weeks. CsA 15 mg/kg treatment increased blood levels of tHcy. Both CsA treatments (5mg/kg and 15 mg/kg) decreased adenine nucleotides hydrolysis by ecto-nucleotidases in serum, which negatively correlated with tHcy levels (r: -0.74, r: -0.63 and r: -0.63, p<0.004, for ATP, ADP and AMP, respectively). CsA 15mg/kg induced a statistically significant increase in ADP and decrease in adenosine (ADO) plasma levels compared to control group. THcy levels were positively correlated with plasma ADP levels and negatively correlated with ADO levels (r: 0.84, p<0.0001 and r: -0.68, p<0.0001, respectively). Rats under CsA 15 mg/kg treatment presented cell injury and inflammatory responses in the endothelium and intima layer of the aorta artery. In conclusion, blood ecto-nucleotidases activity, tHcy, and ADP and ADO levels may be implicated in vascular injury induced by CsA treatment.
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PMID:Chronic treatment with cyclosporine affects systemic purinergic parameters, homocysteine levels and vascular disturbances in rats. 2059 30


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