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:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinemia and insulin resistance are independent factors for cardiovascular disease. Most of the angiotoxic effects of homocysteine are related to the formation of homocysteine thiolactone and the consequent increase in oxidative stress. We have recently found that homocysteine thiolactone inhibits insulin receptor tyrosine kinase activity, which results in decreased phosphatidylinositol 3-kinase (PI3K) activity and inhibition of glycogen synthesis. Oxidative stress seemed to be the mechanism underlying these effects, since glutathione was able to restore the insulin signaling as well as the insulin-mediated glycogen synthesis. In the present work we have further investigated insulin receptor signaling studying mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation. Again, homocysteine thiolactone (50 microM) prevented insulin-mediated MAPK, GSK-3 and p70 S6K phosphorylation and these effects were blocked by glutathione (250 microM). Since MAPK and PI3K pathways, including GSK3 and S6K, seem to mediate insulin-mediated growth and proliferation, we measured DNA and protein synthesis. We have found that homocysteine thiolactone (50 microM) inhibits insulin-mediated growth and proliferation, as previously shown for glycogen synthesis. Again, these effects seem to be mediated by oxidative stress, since 250 microM glutathione completely abolished the effects of homocysteine thiolactone on insulin-stimulated DNA and protein synthesis. In conclusion, these data suggest that homocysteine thiolactone impairs insulin signaling by a mechanism involving oxidative stress, leading to a defect in the action of insulin on growth and proliferation.
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PMID:Homocysteine thiolactone inhibits insulin-stimulated DNA and protein synthesis: possible role of mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation. 1569 82

Reduced arterial compliance and increased pulse pressure are common and major risk factors for cardiovascular disease. Here, we reveal a novel mechanism whereby loss of wall distensibility blunts endothelial cell protection to oxidant stress-induced apoptosis. Bovine aortic endothelial cells cultured in compliant or stiff silastic tubes were pulse perfused by arterial pressure/flow waveforms generated by a servo-pump. Pulse perfusion induced time-dependent Akt activation peaking >6-fold after 2 hours in compliant tubes and a similar time course but half the magnitude in stiff tubes. This was accompanied by quantitatively similar disparities in phosphoinositide-3 kinase activation and in Akt-stimulated suppressors of apoptosis: glycogen synthase kinase-3beta, forkhead, and Bad. Cells perfused in compliant tubes had twice the protection against H2O2-stimulated apoptosis than those in stiffer tubes. This protection was lost by pretreatment with an Akt inhibitor and restored in cells transfected with myristoylated Akt yet perfused in stiff tubes. Shear and stretch Akt signaling coupled to different upstream pathways as inhibition of vascular endothelial growth factor receptor 2 (VEGF2R) or disruption of caveolae blocked steady and pulse flow-mediated activation, yet did not suppress phosphorylated Akt induced by pulse perfusion in compliant tubes (concomitant stretch). Unlike Akt, reactive oxygen species, activated nuclear factor kappaB, and suppression of H2O2-stimulated c-Jun-N-terminal kinase activity were similar in pulse-perfused compliant and stiff tubes. Thus, cyclic endothelial cell stretch by pulse perfusion enhances Akt-dependent antiapoptosis above that induced by steady or phasic shear stress and, unlike the latter, signals via a VEGF2R/caveolae-independent pathway. Enhancing this stretch pathway may prove useful for improving endothelial function in stiff arteries.
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PMID:Reduced wall compliance suppresses Akt-dependent apoptosis protection stimulated by pulse perfusion. 1610 43

Diabetes mellitus (DM) is a significant healthcare concern worldwide that affects more than 165 million individuals leading to cardiovascular disease, nephropathy, retinopathy, and widespread disease of both the peripheral and central nervous systems. The incidence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose levels raises future concerns in regards to the financial and patient care resources that will be necessary to care for patients with DM. Interestingly, disease of the nervous system can become one of the most debilitating complications and affect sensitive cognitive regions of the brain, such as the hippocampus that modulates memory function, resulting in significant functional impairment and dementia. Oxidative stress forms the foundation for the induction of multiple cellular pathways that can ultimately lead to both the onset and subsequent complications of DM. In particular, novel pathways that involve metabotropic receptor signaling, protein-tyrosine phosphatases, Wnt proteins, Akt, GSK-3beta, and forkhead transcription factors may be responsible for the onset and progression of complications form DM. Further knowledge acquired in understanding the complexity of DM and its ability to impair cellular systems throughout the body will foster new strategies for the treatment of DM and its complications.
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PMID:Mechanistic insights into diabetes mellitus and oxidative stress. 1762 10

Cardiovascular disease (CVD) is the most critical global health threat, which contributes more than one third of global morbidity. CVD includes heart disease, vascular disease, atherosclerosis, stroke and hypertension. The most important independent risk factors for CVD include dyslipidemia along with hypertension, obesity, sedentary lifestyle, diabetes and chronic inflammation. These factors are directly regulated by diet, metabolism and physical activity. Diets rich in fat and carbohydrate coupled to sedentary lifestyles have contributed to the increase in dyslipidemia, type 2 diabetes, obesity and CVD in the world. Discovery of Peroxisome Proliferator Activated Receptors (PPARs) as a key regulator of metabolic pathways has led to significant insight into the mechanisms regulating these processes. Three PPAR subtypes, encoded by distinct genes, are designated as PPAR-alpha, PPAR-delta (also know as beta) and PPAR-gamma. PPARs act as nutritional sensors that regulate a variety of homeostatic functions including metabolism, inflammation and development. PPAR-alpha is the main metabolic regulator for catabolism whereas PPAR-gamma regulates anabolism or storage. PPARs are expressed in the cardiovascular system such as endothelial cells, vascular smooth muscle cells and monocytes/macrophages. It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. In 1997, a Glaxo patent described that Troglitazone (first PPAR-gamma ligand to reach market) reduced TNF-induced VCAM1 expression in HUVECs indicating the potential benefit in atherosclerosis. A series of patents from Eli Lilly and Dr. Reddy's Laboratories Ltd. between 1999 and 2005 described a variety of PPAR-alpha and -alpha,gamma dual ligands in a number of patents having glucose, triglyceride, cholesterol lowering, HDL elevating and body weight reducing activity. Patents from Metabolex and Tularik in 2001 and 2002 described the beneficial effects of SPPARM molecules for insulin resistance and diabetes, without showing concern on PPAR-gamma related side effects such as edema and body weight. GSK and Takeda described the potential effects of PPAR-delta modulators during 2001 to 2004 in few patents. Several clinical and preclinical studies have demonstrated the beneficial effects of PPAR ligands on various cardiovascular risk factors. This review intends to capture some of the key studies in this area as is described in some recent patents and literature.
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PMID:Role of PPAR in cardiovascular diseases. 1822 Oct 86

Endothelial lipase (EL) is a 482-amino-acid protein from the triglyceride lipase gene family that uses a Ser-His-Asp triad for catalysis. Its expression in endothelial cells and preference for phospholipids rather than triglycerides are unique. Animal models in which it is overexpressed or knocked out indicate EL levels are inversely correlated with high-density lipoprotein cholesterol (HDL-C). HDL-C is commonly referred to as the good form of cholesterol because it is involved in the reverse cholesterol transport pathway, in which excess cholesterol is effluxed from peripheral tissues for excretion or reabsorption. Thus, EL inhibition in humans is expected to lead to increases in HDL levels and possibly a decrease in cardiovascular disease. To discover inhibitors of EL, a coupled assay for EL has been developed, using its native substrate, HDL. Hydrolysis of HDL by EL yields free fatty acids, which are coupled through acyl-CoA synthetase, acyl-CoA oxidase, and horseradish peroxidase to produce the fluorescent species resorufin. This assay was developed into a 5-microL, 1536-well assay format, and a high-throughput screen was executed against the GSK collection. In addition to describing the screening results, novel post-HTS mechanism-of-action studies were developed for EL and applied to 1 of the screening hits as an example.
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PMID:A high-throughput screen for endothelial lipase using HDL as substrate. 1856 79

The evidence is compelling for a role of inflammation in cardiovascular diseases; however, the chronic use of anti-inflammatory drugs for these indications has been disappointing. The recent study compares the effects of two anti-inflammatory agents [cyclooxygenase 2 (COX2) and p38 inhibitors] in a model of cardiovascular disease. The vascular, renal, and cardiac effects of 4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one (rofecoxib; a COX2 inhibitor) and 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide [GSK-AHAB, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor], were examined in the spontaneously hypertensive stroke-prone rat (SHR-SP). In SHR-SPs receiving a salt-fat diet (SFD), chronic treatment with GSK-AHAB significantly and dose-dependently improved survival, endothelial-dependent and -independent vascular relaxation, and indices of renal function, and it attenuated dyslipidemia, hypertension, cardiac remodeling, plasma renin activity (PRA), aldosterone, and interleukin-1beta (IL-1beta). In contrast, chronic treatment with a COX2-selective dose of rofecoxib exaggerated the harmful effects of the SFD, i.e., increasing vascular and renal dysfunction, dyslipidemia, hypertension, cardiac hypertrophy, PRA, aldosterone, and IL-1beta. The protective effects of a p38 MAPK inhibitor are clearly distinct from the deleterious effects of a selective COX2 inhibitor in the SHR-SP and suggest that anti-inflammatory agents can have differential effects in cardiovascular disease. The results also suggest a method for evaluating long-term cardiovascular efficacy and safety.
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PMID:Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. 1955 50

Inhibition of cardiac hypertrophy leads to a significant reduction in cardiovascular mortality and morbidity. Quercetin is by far the most abundant flavonoid and believed to ameliorate cardiovascular disease. Therefore, we investigated whether quercetin supplementation could attenuate the development of cardiac hypertrophy induced by pressure overload. Three weeks after suprarenal transverse abdominal aortic constriction, heart to body weight (HW/BW) ratio increased compared to the sham group (3.40 +/- 0.06 mg/g versus 2.83 +/- 0.02 mg/g, P<0.001). The quercetin administered group showed complete inhibition of cardiac hypertrophy (2.85 +/- 0.01 mg/g, P<0.001). Malonyldialdehyde production induced by pressure overload was suppressed by quercetin. The activities of extracellular signal-regulated kinase (ERK1/2), p38 MAP kinase, Akt and GSK-3beta were significantly increased with pressure overload and attenuated by quercetin treatment. We conclude that quercetin appears to block the development of cardiac hypertrophy induced by pressure overload in rats and that these effects may be mediated through reduced oxidant status and inhibition of ERK1/2, p38 MAP kinase, Akt and GSK-3beta activities.
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PMID:Quercetin prevents cardiac hypertrophy induced by pressure overload in rats. 1957 81

Leukotrienes are lipid inflammatory mediators that are implicated in asthma, COPD, arthritis, cardiovascular disease and cancer. Leukotriene synthesis requires 5-lipoxygenase activating protein (FLAP), which acts as a scaffolding protein for the assembly of other enzymes involved in the leukotriene synthetic pathway occurring at the nuclear envelope of leukocytes. By blocking the formation of both leukotriene B4 and the cysteinyl leukotrienes (ie, LTC4 , LTD4 and LTE4), FLAP inhibitors act as broad-spectrum leukotriene-modifier drugs that may have a wide range of therapeutic applications. FLAP inhibitors such as MK-886, MK-0591 and veliflapon (BAY-X-1005, DG-031) demonstrated promise in clinical trials with patients with inflammatory diseases in the mid 1990 s, but, unlike the 'lukast' class of cysteinyl-leukotriene receptor antagonists, these compounds were not brought to market. The elucidation of the 3D structure of FLAP has enabled novel compound development, and several FLAP inhibitors including 2190914 (AM-103) and GSK-2190915 (both under development by GlaxoSmithKline plc) have entered phase II trials for the treatment of inflammatory disease, including asthma.
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PMID:FLAP inhibitors for the treatment of inflammatory diseases. 1987 84

Premenopausal women have less cardiovascular disease and lower cardiovascular morbidity and mortality than men the same age. Our previous studies showed that female mice have lower mortality and better preserved cardiac function after myocardial infarction. However, the precise cellular and molecular mechanisms responsible for such a sex difference are not well established. Using cultured adult mouse cardiomyocytes, we tested the hypothesis that the survival advantage of females stems from activated estrogen receptors and Akt survival signaling pathways. Adult mouse cardiomyocytes were isolated from male and female C57BL/6J mice and treated with hydrogen peroxide (100 micromol/L) for 30 minutes. Cell survival was indicated by rod ratio (rod shaped cells:total cells), cell death by lactate dehydrogenase release, and positive staining of annexin-V (a marker for apoptosis) and propidium iodide (a marker for necrosis). In response to hydrogen peroxide(,) female adult mouse cardiomyocytes exhibited a higher rod ratio, lower lactate dehydrogenase release, and fewer Annexin-V-positive and propidium iodide-positive cells compared with males. Phospho-Akt was greater in females both at baseline and after hydrogen peroxide stimulation. The downstream molecule of Akt, phosphor-GSK-3beta (inactivation), was also higher, whereas caspase 3 activity was lower in females in response to hydrogen peroxide. Bcl-2 did not differ between sexes. Estrogen receptor-alpha was the dominant isoform in females, whereas estrogen receptor-beta was low but similar in both sexes. Our findings demonstrate that female adult mouse cardiomyocytes have a greater survival advantage when challenged with oxidative stress-induced cell death. This may be attributable to activation of Akt and inhibition of GSK-3beta and caspase 3 through an estrogen receptor-alpha-mediated mechanism.
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PMID:Female adult mouse cardiomyocytes are protected against oxidative stress. 2021 61

There is a growing need for pharmacological agents to manage cardiovascular disease in the rapidly growing elderly population. Here, we determine if acetaminophen is efficacious in decreasing age-related increases in cardiac reactive oxygen species (ROS) and apoptosis in aging Fischer 344 X Brown Norway rats. Compared to 6-month control animals, indices of oxidative (superoxide anion [O2( *-)] and 4-hydroxy-2-nonenal [4-HNE]) and nitrosative (protein nitrotyrosylation) stress were markedly increased in 33-month-old rat hearts. 33-month animals that had been treated with acetaminophen (30 mg/kg/day p.o. for 6 months) exhibited diminished age-related increases in cardiac ROS levels and TUNEL positive nuclei and these changes were accompanied by improvements in the Bax/Bcl2 ratio, diminished evidence of caspase-3 activation and increased phosphorylation of protein kinase B, ERK1/2, p70S6K and GSK-3beta. Taken together these results suggests that acetaminophen may attenuate the age-associated increases in the cardiomyocyte apoptosis, possibly via diminishing age associated elevation in ROS production.
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PMID:Chronic acetaminophen attenuates age-associated increases in cardiac ROS and apoptosis in the Fischer Brown Norway rat. 2040 80


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