Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphatidylinositol 3-kinase (PI3K) activity is increased in aortae from deoxycorticosterone (DOCA)-salt rats and enhanced PI3K activity contributes to the arterial hyperreactivity in these animals. Because PI3K activity is increased in DOCA-salt hypertension, we postulated that phosphorylation of Akt and glycogen synthase kinase 3 (GSK-3), serine threonine kinases that are downstream of PI3K, would be increased in DOCA-salt hypertension. In this study, we focused on GSK-3. Because GSK-3 activity is reduced by phosphorylation, we expected that its activity would be reduced in DOCA-salt hypertensive arteries and that reduced GSK-3 activity could contribute to enhanced adrenergic signaling and vascular smooth muscle hypertrophy that augment the heightened contractile response in DOCA-salt hypertension. Surprisingly, we observed a decrease in phosphorylation of GSK-3, indicating an increase in GSK-3 activity. To determine whether increased GSK-3 activity contributes to altered arterial reactivity in DOCA-salt animals, we measured isometric contraction to norepinephrine (NE) in the presence and absence of PI3K or GSK-3 inhibition. Addition of LY294002 (20 micromol/L), a PI3K inhibitor, resulted in a rightward shift in response to NE and normalized the NE-induced contractions in the DOCA hypertensive vessels. SB415286, a GSK-3 inhibitor, resulted in a slight rightward shift in response to NE in the DOCA-salt vessels. Thus, enhanced GSK-3 activity modestly augments the effects of PI3K but does not appear to contribute greatly to the altered arterial reactivity in DOCA-salt hypertension.
Hypertension 2003 Apr
PMID:PI3-kinase-induced hyperreactivity in DOCA-salt hypertension is independent of GSK-3 activity. 1262 35

Lipocalin-type prostaglandin D2 synthase (L-PGDS) has recently been linked to a variety of pathophysiological cardiovascular conditions including hypertension and diabetes. In this study, we report on the 50% increase in L-PGDS protein expression observed in vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR). L-PGDS expression also increased 50% upon the differentiation of normotensive control cells (WKY, from Wistar-Kyoto rats). In addition, we demonstrate differential effects of L-PGDS treatment on cell proliferation and apoptosis in VSMCs isolated from SHR versus WKY controls. L-PGDS (50 microg/ml) was able to significantly inhibit VSMC proliferation and DNA synthesis and induce the apoptotic genes bax, bcl-x, and ei24 in SHR but had no effect on WKY cells. Hyperglycemic conditions also had opposite effects, in which increased glucose concentrations (20 mm) resulted in decreased L-PGDS expression in control cells but actually stimulated L-PGDS expression in SHR. Furthermore, we examined the effect of L-PGDS incubation on insulin-stimulated Akt, glycogen synthase kinase-3beta (GSK-3beta), and ERK phosphorylation. Unexpectedly, we found that when WKY cells were pretreated with L-PGDS, insulin could actually induce apoptosis and failed to stimulate Akt/GSK-3beta phosphorylation. Insulin-stimulated ERK phosphorylation was unaffected by L-PGDS pretreatment in both cell lines. We propose that L-PGDS is involved in the balance of VSMC proliferation and apoptosis and in the increased expression observed in the hypertensive state is an attempt to maintain a proper equilibrium between the two processes via the induction of apoptosis and inhibition of cell proliferation.
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PMID:Prostaglandin D2 synthase inhibits the exaggerated growth phenotype of spontaneously hypertensive rat vascular smooth muscle cells. 1268 6

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart. The effects of AM on GSK-3beta and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3beta but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
Hypertension 2004 Jan
PMID:Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. 1466 48

Because adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP), we inquired whether HBP activation affects pancreatic beta-cell survival. Exposure of human islets to high glucose resulted in increased apoptosis of beta-cells upon serum deprivation that was reversed by azaserine. Also, glucosamine, a direct precursor of the downstream product of the HBP, increased human beta-cells apoptosis upon serum deprivation, which was reversed by benzyl-2-acetamido-2-deoxy-alpha-d-galactopyranoside (BADGP), an inhibitor of protein O-glycosylation. These results were reproduced in RIN rat beta-cells. Glucosamine treatment resulted in inhibition of tyrosine-phosphorylation of the insulin receptor (IR), IRS-1, and IRS-2, which was associated with increased O-glycosylation. These changes caused impaired activation of the PI 3-kinase/Akt survival signaling that resulted in reduced GSK-3 and FOXO1a inactivation. BADGP reversed the glucosamine-induced reduction in insulin-stimulated phosphorylation of IR, IRS-1, IRS-2, Akt, GSK-3, and FOXO1a. Impaired FOXO1a inactivation sustained expression of the pro-apoptotic protein Bim, without affecting Bad, Bcl-XL, or Bcl-2 expression. These results indicate that hyperglycemia may increase susceptibility to apoptosis of human and rat beta-cell through activation of the HBP. Increased routing of glucose through this metabolic pathway results in impaired activation of the IR/IRSs/PI3-kinase/Akt survival pathway by induction of O-glycosylation of signaling molecules.
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PMID:Increased O-glycosylation of insulin signaling proteins results in their impaired activation and enhanced susceptibility to apoptosis in pancreatic beta-cells. 1505 79

Several opinion leaders have monitored their blood pressure systematically a sufficient number of times a day for chronomic (time structural) analyses, from the time of encountering chronobiology until their death; they set an example for others who also may not wish to base treatment on single spotchecks in a health care office. Such self-measurements, while extremely helpful, were not readily feasible without a noteworthy interruption of activities during waking as well as of sleep. New, relatively unobtrusive instrumentation now makes monitoring possible and cost-effective and will save lives. Illustrative results and problems encountered in an as-one-goes self-survey by GSK, a physician-scientist, are presented herein. Both MESOR-hypertension and CHAT (circadian hyper-amplitude-tension) can be intermittent conditions even under treatment, and treatment is best adjusted based on monitoring, rather than "flying blind".
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PMID:Why continued surveillance? Intermittent blood pressure and heart rate abnormality under treatment. 1627 83

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

Metabolic syndrome and type 2 diabetes are progressive, indolent, multi-organ diseases. Understanding the abnormalities of heat shock proteins (HSPs) in these diseases is paramount to understanding their pathogenesis. In insulin resistant states and diabetes, heat shock factor 1(HSF-1) is low in insulin sensitive tissues, resulting in low Hsp 60, 70, and 90 levels. We propose that low Hsps levels are the result of decreased insulin action leading to less phosphorylation of PI3K, PKB, and glycogen synthase kinase-3 (GSK-3). Importantly, less GSK-3 phosphorylation (and thus more GSK-3 activity) will lower HSF-1. Low Hsps make organs vulnerable to injury, impair the stress response, accelerate systemic inflammation, raise islet amyloid polypeptide, and increase insulin resistance. Feeding this cycle is excess saturated fat and calorie consumption, hypertension, inactivity, aging, and genetic predisposition- all of which are a associated with high GSK-3 activity and low Hsps. Support for the proposed "vicious" cycle is based on the observation that GSK-3 inhibition and Hsp stimulation result in increased insulin sensitivity, reduced accumulation of degenerative proteins with in the cell, improved wound healing, decreased organ damage and improved recovery from vascular ischemia. Recognizing GSK-3 and Hsps in the pathogenesis of insulin resistance, the central common feature of the metabolic syndrome, and type 2 diabetes will expand our understanding of the disease, offering new therapeutic options.
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PMID:Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis. 1837 Jul 76

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

Oxidative stress is characterized as an imbalance between the cellular production of oxidants and the cellular antioxidant defenses and contributes to the development of numerous cardiovascular and metabolic disorders, including hypertension and insulin resistance. The effects of prolonged oxidant stress in vitro on the insulin-dependent glucose transport system in mammalian skeletal muscle are not well understood. This study examined the in vitro effects of low-level oxidant stress (60-90 microM, H(2)O(2)) for 4 h on insulin-stimulated (5 mU/ml) glucose transport activity (2-deoxyglucose uptake) and on protein expression of critical insulin signaling factors (insulin receptor (IR), IR substrates IRS-1 and IRS-2, phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3 (GSK-3)) in isolated soleus muscle of lean Zucker rats. This oxidant stress exposure caused significant (50%, p<0.05) decreases in insulin-stimulated glucose transport activity that were associated with selective loss of IRS-1 (59%) and IRS-2 (33%) proteins, increased (64%) relative IRS-1 Ser(307) phosphorylation, and decreased phosphorylation of Akt Ser(473) (50%) and GSK-3beta Ser(9) (43%). Moreover, enhanced (37%) phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was observed. Selective inhibition of p38 MAPK (10 microM A304000) prevented a significant portion (29%) of the oxidant stress-induced loss of IRS-1 (but not IRS-2) protein and allowed partial recovery of the impaired insulin-stimulated glucose transport activity. These results indicate that in vitro oxidative stress in mammalian skeletal muscle leads to substantial insulin resistance of distal insulin signaling and glucose transport activity, associated with a selective loss of IRS-1 protein, in part due to a p38 MAPK-dependent mechanism.
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PMID:Oxidant stress-induced loss of IRS-1 and IRS-2 proteins in rat skeletal muscle: role of p38 MAPK. 1970 55

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.
Hypertension 2010 May
PMID:Female adult mouse cardiomyocytes are protected against oxidative stress. 2021 61


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