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

Administration of glucocorticoids results in hypertension, cardiac hypertrophy, and general myopathy. The present study analyzed the acute effect of dexamethasone (0.5 mg/100 g for 3 days) or dexamethasone plus insulin-like growth factor-1 (0.35 mg/100 g for 3 days) on differential gene expression in the gastrocnemius muscle and the left ventricular myocardium of rats. Dexamethasone induced atrophy of gastrocnemius muscle. Cathepsin L, and not ubiquitin, was the earliest mediator of skeletal muscle proteolysis induced by dexamethasone. Insulin-like growth factor-1 reversed gastrocnemius muscle mass, and deleted a part of downregulated genes by dexamethasone. On the other hand, dexamethasone administration did not result in cardiac hypertrophy or hypertension. Only prostaglandin D synthase gene was upregulated by dexamethasone in myocardium, and genes related to extracellular matrix and proteinase inhibitor were downregulated. Molecular alteration for hypertrophy might have initiated. Dexamethasone-induced proteolysis and reversal with insulin-like growth factor-1 occurred rapidly in skeletal muscle; but was relatively delayed in the myocardium.
 ...
PMID:Differential gene expression in the rat skeletal and heart muscle in glucocorticoid-induced myopathy: analysis by microarray. 1461 91

Prostaglandin D(2) (PGD(2)) and its metabolites bind to the intracellular PPARs to regulate vasoactive substances involved in vascular remodeling through regulation of mRNAs transcription as well as through receptor-mediated mechanisms. PGD(2) decreases inducible NO, PAI-1, endothelin, and VCAM expression through inhibition to NF kappa B, STAT, or AP-1 transcription factors, which are regulated by cytokines/immune system. Moreover, transfer of L-PGDS (PGD(2) synthase) into the intracellular space of EC or SMC increases intracellular PGD(2), thereby decreasing these substances. PGD(2) attenuates in vivo organ injury mediated by cytokines and the immune system. The pretreatment with PGD(2) attenuates the liver damage and hemodynamic collapse following LPS. Dahl salt-sensitive rats, with decreased PGD(2) in the outer medulla of the kidney, are prone to hypertensive kidney injury. Serum L-PGDS level is increased in renal dysfunction through a decrease in glomerular filtration. L-PGDS in urine may be derived from a failure of tubular reabsorption or from in situ synthesis. Urinary L-PGDS excretion markedly increases in the early stage of kidney injury, and urinary L-PGDS is a useful predictor of the forthcoming renal injury. Indeed, urinary L-PGDS precedes clinically overt proteinuria or other parameters indicating renal dysfunction in hypertension, primary renal diseases, and diabetes in humans. PGD(2)/L-PGDS system is a Cinderella of vascular biology.
 ...
PMID:[PGD(2)/L-PGDS system in hypertension and renal injury]. 1469 55

Prostaglandins (PGs) of the J2 family including PGJ2, delta12-PGJ2, and 15-deoxy-delta12,14-PGJ2 (15d-PGJ2) are naturally occurring metabolites of PGD2. Among them, 15d-PGJ2 is a powerful ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). 15d-PGJ2 and synthetic PPARgamma ligands have been reported to exert several effects on vascular cells, such as anti-proliferative, differentiation-inducing, anti-apoptotic, and anti-inflammatory effects, most of which seem to be atheroprotective, although PPARgamma-independent mechanisms may be involved. Vascular endothelial cells, intimal smooth muscle cells, and cardiomyocytes express lipocalin-type PGD synthase (L-PGDS) in vivo, which catalyzes the isomeric conversion of PGH2 to PGD2. L-PGDS expression in endothelial cells is stimulated by laminar fluid shear stress. PGD2 and 15d-PGJ2 are detected in the culture medium of endothelial cells exposed to shear stress. Serum and urinary levels of L-PGDS increase in diseases with vascular injuries, such as hypertension and diabetes. Based on these findings, we hypothesize that PGs of the J2 series are physiological substances produced in the vascular wall to protect vascular cells from injurious stimuli and to repress inflammatory reactions. If this hypothesis is correct, PGJ2 family members or other similar substances may provide novel preventive and therapeutic strategies for the treatment of vascular diseases.
 ...
PMID:Prostaglandin J2 family and the cardiovascular system. 1532 May 11

Cyclooxygenase-2 selective inhibitors (COXIBs) were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2 (PGH2) and other prostaglandin (PG) metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2 from arachidonate, PGH2 is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2 (TXA2). These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2 in vitro, the ultimate prostanoids they produce in vivo may be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF), promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.
 ...
PMID:Adverse effects of COX-2 inhibitors. 1611 40

Accumulating evidence indicates cyclooxygenase (COX) 1 and COX2 differentially regulate cardiovascular and renal function. We have demonstrated previously in mice that COX2 inhibition enhances angiotensin II-induced hypertension, and COX1 inhibition attenuates the pressor effect of angiotensin II. To further elucidate the mechanism underlying the functional difference of COX1 versus COX2 inhibition, the present studies examined the prostaglandin (PG) profiles derived in COX1- or COX2-inhibited mouse kidney and aorta using gas chromatographic/mass spectrometric assays. PGE2 is the most abundant prostanoid in both renal cortex and medulla in normal C57BL/6J mice, followed by PGI2, PGF2alpha and thromboxane A2. In contrast PGI2 was most abundant in aorta followed by thromboxane A2, PGE2, and PGF2alpha. PGD2 was undetectable in control kidney or aorta. At baseline, inhibition of COX1 decreased total prostaglandins in renal cortex, medulla, and aorta, whereas COX2 inhibition decreased total prostaglandins only in renal medulla. Angiotensin II infusion significantly increased COX2-dependent/COX1-independent PGE2 and PGI2 in renal cortex and medulla. Angiotensin II also significantly increased renal PGF2alpha in cortex, but not in medulla, through both COX1- and COX2-dependent mechanisms. These studies demonstrate that although COX1 primarily contributes to basal prostanoid production in the kidney and aorta, angiotensin II increases renal vasodilator prostanoids predominately via COX2 activity. These effects may contribute to the specific effect of COX2 inhibitors to increase blood pressure.
Hypertension 2006 Aug
PMID:Differentiation of cyclooxygenase 1- and 2-derived prostanoids in mouse kidney and aorta. 1680 85

Soluble epoxide hydrolases catalyze the hydrolysis of epoxides in acyclic systems. In man this enzyme is the product of a single copy gene (EPXH-2) present on chromosome 8. The human sEH is of interest due to emerging roles of its endogenous substrates, epoxygenated fatty acids, in inflammation and hypertension. One of the consequences of inhibiting sEH in rodent inflammation models is a profound decrease in the production of pro-inflammatory and proalgesic lipid metabolites including prostaglandins. This prompted us to hypothesize that sEH inhibitors may have antinociceptive properties. Here we tested if sEH inhibitors can reduce inflammatory pain. Hyperalgesia was induced by intraplantar LPS injection and sEH inhibitors were delivered topically. We found that two structurally dissimilar but equally potent sEH inhibitors can be delivered through the transdermal route and that sEH inhibitors effectively attenuate thermal hyperalgesia and mechanical allodynia in rats treated with LPS. In addition we show that epoxydized arachidonic acid metabolites, EETs, are also effective in attenuating thermal hyperalgesia in this model. In parallel with the observed biological activity metabolic analysis of oxylipids showed that inhibition of sEH resulted with a decrease in PGD2 levels and sEH generated degradation products of linoleic and arachidonic acid metabolites with a concomitant increase in epoxides of linoleic acid. These data show that inhibition of sEH may become a viable therapeutic strategy to attain analgesia.
 ...
PMID:Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain. 1696 14

CSF is thought to flow continuously from the site of production in the ventricles into interconnected spaces; i.e. cisterns and subarachnoid spaces (SASs). Since the SAS of the optic nerve is defined by a cul-de-sac anatomy, it is not evident how local CSF might recycle from that region to the general SAS. The concept of free communication of CSF has recently been challenged by the description of a concentration gradient of beta-trace protein, a lipocalin-like prostaglandin d-synthase (L-PGDS), between the spinal CSF and that in the SAS of the optic nerve, indicating diminished local clearance or local overproduction of L-PGDS here. In fact, computed cisternography with a contrast agent in three patients with idiopathic intracranial hypertension and asymmetric papilloedema demonstrate a lack of contrast-loaded CSF in the SAS of the optic nerve despite it being present in the intracranial SAS, thus suggesting compartmentation of the SAS of the optic nerve. The concept of an optic nerve compartment syndrome is further supported by a concentration gradient of brain-derived L-PGDS between the spinal CSF and the CSF from the optic nerve SAS in the same patients.
 ...
PMID:Cerebrospinal fluid dynamics between the intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional? 1711 96

Lipocalin-type prostaglandin D(2) synthase (L-PGDS) is a highly glycosylated protein found in several body fluids. Elevated L-PGDS levels have been observed in the serum of patients with renal impairment, diabetes mellitus, and hypertension. Recently, we demonstrated the ability of L-PGDS to induce apoptosis in a variety of cell types including epithelial cells, neuronal cells, and vascular smooth muscle cells (VSMCs). The aim of this study was to investigate the effect several site-directed mutations had on L-PGDS-induced apoptosis in order to identify potential sites of regulation. Point mutations created in a glycosylation site (Asn51), a protein kinase C phosphorylation site (Ser106), and the enzymatic active site (Cys65) all inhibited L-PGDS-induced apoptosis as determined by both terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and caspase3 activity. We also compared the L-PGDS isoforms present in GK rat serum to WKY control serum using two-dimensional gel electrophoresis and observed distinct differences which vanished after PNGase F glycolytic digestion. We conclude that post-translational modification of L-PGDS, by either glycosylation or phosphorylation, enhances its apoptotic activity and inhibits VSMC hyperproliferation and postulate that this process is altered in type 2 diabetes.
 ...
PMID:Post-translational modification regulates prostaglandin D2 synthase apoptotic activity: characterization by site-directed mutagenesis. 1725 69

The present study was designed to assess whether or not changes in genomic expression of cyclooxygenases (COX-1, COX-2), endothelial nitric oxide synthase (eNOS), and prostanoid synthases in the endothelium and of prostanoid receptors in vascular smooth muscle contribute to the occurrence of endothelium-dependent contractions during aging and hypertension. Gene expression was quantified by real-time PCR using isolated endothelial cells and smooth muscle cells (SMC) from the aorta of Wistar-Kyoto and spontaneously hypertensive rats. Genes for all known prostanoid synthases and receptors were present in endothelial cells and SMC, respectively. Aging caused overexpression of eNOS, COX-1, COX-2, thromboxane synthase, hematopoietic-type prostaglandin D synthase, membrane prostaglandin E synthase-2, and prostaglandin F synthase in endothelial cells and COX-1 and prostaglandin E(2) (EP)(4) receptors in SMC. Hypertension augmented the expression of COX-1, prostacyclin synthase, thromboxane synthase, and hematopoietic-type prostaglandin D synthase in endothelial cells and prostaglandin D(2) (DP), EP(3), and EP(4) receptors in SMC. The increase in genomic expression of endothelial COX-1 explains why in aging and hypertension the endothelium has greater propensity to release cyclooxygenase-derived vasoconstrictive prostanoids. The expression of prostacyclin synthase was by far the most abundant, explaining why the majority of the COX-1-derived endoperoxides are transformed into prostacyclin, substantiating the role of prostacyclin as an endothelium-derived contracting factor. The expression of thromboxane synthase was increased in the cells of aging or hypertensive rats, explaining why the prostanoid can contribute to endothelium-dependent contractions. It is uncertain whether the gene modifications caused by aging and hypertension directly contribute to endothelium-dependent contractions or rather to vascular aging and the vascular complications of the hypertensive process.
 ...
PMID:Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. 1805 86

Recent studies suggest that lipocalin-type prostaglandin (PG) D synthase (L-PGDS), which converts PGH2 to PGD2, is implicated in the pathogenesis of atherosclerosis. However, clinical evidence for the association between serum L-PGDS levels and atherosclerosis has not been reported. In this study, we measured the serum L-PGDS concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and investigated the association with traditional cardiovascular risk factors and surrogate atherosclerotic indices, such as the maximum score of the intima-media complex thickness of the carotid artery (C-IMT(max)) and the brachial-ankle pulse wave velocity (ba-PWV), in 500 non-treated asymptomatic subjects. The serum concentration of L-PGDS was 0.56+/-0.01 (mean+/-SEM, range 0.25-1.27, median 0.54) mg/L. Serum L-PGDS levels increased with age and were higher in men than in women. Serum L-PGDS was higher in subjects with hypertension and increased with increasing numbers of the traditional atherosclerotic risk factors. When the subjects were divided into four groups according to the levels of serum L-PGDS, the age-adjusted values of C-IMT(max) and ba-PWV were significantly increased in subjects with higher serum L-PGDS levels (quartile 3 and quartile 4) compared to those in the lowest quartile (quartile 1), for both genders. Multiple regression analysis including risk factors revealed that serum L-PGDS was an independent determinant for ba-PWV (beta=0.130, p<0.001). Serum L-PGDS tended to associate with C-IMT(max) but was not statistically significant (beta=0.084, p=0.075). In conclusion, our results suggest that an increase in serum L-PGDS concentration is associated with the progression of atherosclerosis.
 ...
PMID:Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects. 1901 1


<< Previous 1 2 3 Next >>