Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathological circumstances like inflammation or ischemic insult facilitate the release of adenine nucleotides from several types of cells. These extracellular nucleotides are rapidly converted to adenosine by ectonucleotidases, mainly ectonucleoside triphosphate diphosphohydrolase1 (NTPDase1/CD39) and CD73. NTPDase1/CD39 can interact with caveolins, structural proteins of signal-transducing microdomains termed caveolae. Caveolins are thought to have physiological roles in heart ageing and cardiac diseases. The aim of this study was to investigate the expression of NTPDase1 together with caveolins in chronic human cardiovascular diseases and elucidate their role in human heart. The HPLC analysis showed significant increase in ATPase activity in pathological samples from patients with ischemic heart disease. Immunostaining also showed alterations in the expression and distribution of NTPDase1. Caveolin-1 and caveolin-2 expression was much alike in control and pathological cases, while expression of caveolin-3 was lower in pathological samples. Changes in the expression of NTPDase1 and caveolins seem to be independent of human cardiovascular disease.
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PMID:Expression of NTPDase1 and caveolins in human cardiovascular disease. 1602 70

Extracellular superoxide dismutase (SOD3), a secretory copper enzyme, plays an important role in atherosclerosis and hypertension by modulating the levels of extracellular superoxide anion (O2*-) in the vasculature. Little is known about the mechanisms by which SOD3 obtains its catalytic copper cofactor. Menkes ATPase (MNK) has been shown to transport cytosolic copper to the secretory pathway in nonvascular cells. We performed the present study to determine whether MNK is required for the activation of SOD3 in the vasculature. Here we show that MNK was highly expressed in the various vascular tissues and cells. Aortas and cultured fibroblasts from MNK mutant (MNK(mut)) mice showed a marked decrease in specific activity of SOD3, but not SOD1 (cytosolic form), which was partially restored by copper addition. Copper treatment in wild-type cells promoted the direct interaction and colocalization of SOD3 with MNK in the trans-Golgi network (TGN), suggesting that MNK transports copper to SOD3 in the TGN. Aortas of MNK(mut) mice revealed a decrease in activity of SOD3, but not SOD1, in association with a robust increase in O2*- levels. Finally, both MNK and SOD3 proteins were highly expressed in the intimal lesions of atherosclerotic vessels. In conclusion, vascular MNK plays an essential role in full activity of SOD3 through transporting copper to SOD3 in the TGN, thereby regulating O2*- levels in the vasculature. These studies provide a novel insight into vascular MNK as a critical modulator of "superoxide" stress, which may contribute to cardiovascular disease.
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PMID:Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. 1637 25

Several pathologies of the cardiovascular system are associated with an augmented production of nitric oxide and/or superoxide-derived oxidants and/or alteration in the antioxidant detoxification pathways that lead to nitroxidative stress. One important consequence of these reactive intermediates at the biochemical level is the nitration of protein tyrosines, which is performed through either of two of the relevant nitration pathways that operate in vivo, namely peroxynitrite and heme peroxidase-dependent nitration. Proteins nitrated at tyrosine residues have been detected in several compartments of the cardiovascular system. In this review a selection of nitrated proteins in plasma (fibrinogen, plasmin, Apo-1), vessel wall (Apo-B, cyclooxygenase, prostaglandin synthase, Mn-superoxide dismutase) and myocardium (myofibrillar creatine kinase, alpha-actinin, sarcoplasmic reticulum Ca(2+) ATPase) are analyzed in the context of cardiovascular disease. Nitration of tyrosine can affect protein function, which could directly link nitroxidative stress to the molecular alterations found in disease. While some proteins are inactivated by nitration (e.g. Mn-SOD) others undergo a gain-of-function (e.g. fibrinogen) that can have an ample impact on the pathophysiology of the cardiovascular system. Nitrotyrosine is also emerging as a novel independent marker of cardiovascular disease. Pharmacological strategies directed towards inhibiting protein nitration will assist to shed light on the relevance of this post-translational modification to human cardiovascular pathology.
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PMID:Biochemistry of protein tyrosine nitration in cardiovascular pathology. 1754 86

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, and by resistance to insulin's effects. Such a deficiency results in increased concentrations of glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of diabetes mellitus: Type 1 diabetes (insulin-dependent diabetes, IDDM or juvenile onset diabetes) and Type 2 diabetes (non-insulin-dependent diabetes, NIDDM or adult-onset). Chronic hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C (PKC) isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the retinal, renal, neural and cardiovascular tissues in diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis, cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-ATPase, cPLA(2), PI3Kinase and MAP kinase. Inhibition of PKC, especially the beta1/2 isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that ruboxistaurin, a PKCbeta isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several isoforms is likely to be responsible for some of the pathologies in diabetic retinopathy, nephropathy and cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease with very little side effects.
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PMID:The role of protein kinase C activation and the vascular complications of diabetes. 1757 31

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified that orchestrate a complex process of excitation-contraction coupling and molecular signalling. Despite the variability of the calcium transporters expressed in cardiomyocytes, most calcium channel blockers used therapeutically target the L-type calcium channel and exhibit antihypertensive and/or vasodilating activities. Recently, another calcium pump which is located in the sarcolemma has been shown to mediate cardiac contractility and vascular tone. Interestingly, this sarcolemmal calcium pump (also known as Plasma Membrane Calcium/calmodulin dependent ATPase or PMCA) exerts its function not by altering global calcium concentration, but by mediating signal transduction pathways. This review will discuss recent advances that support the key roles of PMCA as signalling molecule and the potential to target this calcium pump as a novel approach for the treatment of cardiovascular disease.
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PMID:Targeting the sarcolemmal calcium pump: a potential novel strategy for the treatment of cardiovascular disease. 1797 93

Intake of tea flavonoids has been reported to reduce the incidence of cardiovascular disease. The present study was undertaken to investigate the preventive effect of (-)epigallocatechin gallate (EGCG) on heart weight, cardiac marker enzymes, membrane-bound ATPases and electrolytes in isoprenaline (ISO)-induced myocardial infarcted (MI) Wistar rats. Rats subcutaneously administered ISO 100 mgkg(-1) at intervals of 24 h for 2 days resulted in significant increases in heart weight and the activities of cardiac marker enzymes such as creatine kinase, creatine kinase-MB, lactate dehydrogenase (LDH), aspartate transaminase and alanine transaminase in serum, and significant decreases in the activities of these enzymes in the myocardium. ISO injection also increased levels of LDH isoenzymes (LDH 1 and LDH 2). The activity of Na+/K+ ATPase was decreased significantly and the activities of Ca2+ and Mg2+ ATPases were increased significantly in ISO-induced MI rats. Furthermore, the levels of potassium were lowered and the levels of sodium and calcium were increased in ISO-induced MI rats. Prior treatment with EGCG (10, 20 and 30 mgkg(-1)) daily for a period of 21 days reduced the effects of ISO on heart weight, activities of cardiac marker enzymes and membrane bound-ATPases and levels of LDH 1 and LDH 2 and electrolytes. Thus, EGCG exhibits beneficial effects on these enzymes and electrolytes. The observed effects may be due to the antioxidant and membrane-stabilizing effects of EGCG in ISO-induced MI rats.
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PMID:(-)-Epigallocatechin gallate (EGCG) prevents isoprenaline-induced cardiac marker enzymes and membrane-bound ATPases. 1825 Oct 87

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.
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PMID:Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy. 1846 52

Hyperhomocysteinemia is associated with various pathologies including cardiovascular disease, stroke, and cognitive dysfunctions. Systemic administration of homocysteine can trigger seizures in animals, and patients with homocystinuria suffer from epileptic seizures. Available data suggest that homocysteine can be harmful to human cells because of its metabolic conversion to homocysteine thiolactone, a reactive thioester. A number of reports have demonstrated a reduction of Na+/K+-ATPase activity in cerebral ischemia, epilepsy and neurodegeneration possibly associated with excitotoxic mechanisms. The aim of this study was to examine the in vivo effects of D,L-homocysteine and D,L-homocysteine thiolactone on Na+/K+- and Mg2+-ATPase activities in erythrocyte (RBC), brain cortex, hippocampus, and brain stem of adult male rats. Our results demonstrate a moderate inhibition of rat hippocampal Na+/K+-ATPase activity by D,L-homocysteine, which however expressed no effect on the activity of this enzyme in the cortex and brain stem. In contrast, D,L-homocysteine thiolactone strongly inhibited Na+/K+-ATPase activity in cortex, hippocampus and brain stem of rats. RBC Na+/K+-ATPase and Mg2+-ATPase activities were not affected by D,L-homocysteine, while D,L-homocysteine thiolactone inhibited only Na+/K+-ATPase activity. This study results show that homocysteine thiolactone significantly inhibits Na+/K+-ATPase activity in the cortex, hippocampus, and brain stem, which may contribute at least in part to the understanding of excitotoxic and convulsive properties of this substance.
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PMID:The activity of erythrocyte and brain Na+/K+ and Mg2+-ATPases in rats subjected to acute homocysteine and homocysteine thiolactone administration. 1922 40

Reduced nephron endowment is associated with development of renal and cardiovascular disease. We hypothesized this may be attributable to impaired sodium homoeostasis by the remaining nephrons. The present study investigated whether a nephron deficit, induced by fetal uninephrectomy at 100 days gestation (term=150 days), resulted in (i) altered renal sodium handling both under basal conditions and in response to an acute 0.9% saline load (50 ml.kg-1 of body weight.30 min-1); (ii) hypertension and (iii) altered expression of renal channels/transporters in male sheep at 6 months of age. Uninephrectomized animals had significantly elevated arterial pressure (90.1+/-1.6 compared with 77.8+/-2.9 mmHg; P<0.001), while glomerular filtration rate and renal blood flow (per g of kidney weight) were 30% lower than that of the sham animals. Total kidney weight was similar between the groups. Renal gene expression of apical NHE3 (type 3 Na+/H+ exchanger), ENaC (epithelium Na+ channel) beta and gamma subunits and basolateral Na+/K+ ATPase beta and gamma subunits were significantly elevated in uninephrectomized animals, while ENaC alpha subunit expression was reduced. Urine flow rate and sodium excretion increased in both groups in response to salt loading, but this increase in sodium excretion was delayed by approximately 90 min in the uninephrectomized animals, while total sodium output was 12% in excess of the infused load (P<0.05). In conclusion, the present study shows that animals with a congenital nephron deficit have alterations in tubular sodium channels/transporters and cannot rapidly correct for variations in sodium intake probably contributing to the development of hypertension. This suggests that people born with a nephron deficit should be monitored for early signs of renal and cardiovascular disease.
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PMID:Reduced nephron endowment due to fetal uninephrectomy impairs renal sodium handling in male sheep. 2006 44

O-Linked attachment of beta-N-acetyl-glucosamine (O-GlcNAc) on serine and threonine residues of nuclear and cytoplasmic proteins is a highly dynamic posttranslational modification that plays a key role in signal transduction pathways. Preliminary data show that O-GlcNAcylation may represent a key regulatory mechanism in the vasculature, modulating contractile and relaxant responses. Proteins with an important role in vascular function, such as endothelial nitric oxide synthase, sarcoplasmic reticulum Ca(2+)-ATPase, protein kinase C, mitogen-activated protein kinases, and proteins involved in cytoskeleton regulation and microtubule assembly are targets for O-GlcNAcylation, indicating that this posttranslational modification may play an important role in vascular reactivity. Here, we will focus on a few specific pathways that contribute to vascular function and cardiovascular disease-associated vascular dysfunction, and the implications of their modification by O-GlcNAc. New chemical tools have been developed to detect and study O-GlcNAcylation, including inhibitors of O-GlcNAc enzymes, chemoenzymatic tagging methods, and quantitative proteomics strategies; these will also be briefly addressed. An exciting challenge in the future will be to better understand the cellular dynamics of this posttranslational modification, as well as the signaling pathways and mechanisms by which O-GlcNAc is regulated on specific proteins in the vasculature in health and disease.
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PMID:O-GlcNAcylation: a novel post-translational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension. 2040 80


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