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)

Protein kinase C is an important second-messenger system that is translocated from the cytosol to the cell membrane on cell stimulation. We used confocal microscopy to study the spatial distribution of protein kinase C isoforms after stimulation of cultured vascular smooth muscle cells with platelet-derived growth factor and angiotensin II (Ang II). Monoclonal antibodies for the isoforms alpha and beta were used. Translocation was also assessed by Western blot. Isoform alpha was evenly distributed in the cytosol, whereas the beta isoform formed coarse granules in the perinuclear region. Both isoforms shifted from the cytosolic to the membrane fraction after exposure to Ang II (10(-7) mol/L) and platelet-derived growth factor (100 ng/mL at 6, 12, and 20 minutes). Confocal microscopy showed a rapid assembly of isoform alpha along cytosolic fibers at 6 minutes followed by a translocation toward the nucleus at 12 minutes with Ang II. Platelet-derived growth factor engendered a similar response; however, a cytoskeletal distribution was not observed. The beta isoform was rapidly translocated by both inducers to the perinuclear region and the nucleus. Our results show that inducers cause a translocation of protein kinase C isoforms not only into the cell membrane but also into the cell nucleus. We suggest that protein kinase C may also be important for nuclear signaling.
Hypertension 1994 Jun
PMID:Platelet-derived growth factor and angiotensin II induce different spatial distribution of protein kinase C-alpha and -beta in vascular smooth muscle cells. 820 16

Na+,K(+)-ATPase in renal epithelial cells plays an important role in the regulation of Na+ balance, extracellular volume and blood pressure. The function of renal Na+,K(+)-ATPase in Dahl salt-sensitive (DS) rats, an animal model for salt-sensitive hypertension, and Dahl salt-resistant (DR) rats has been studied. In Na+,K(+)-ATPase partially purified from renal cortex, affinities and the Hill coefficients for Na+ and K+ activation were similar in DS and DR rats. Only one component of low ouabain affinity site was found in both strains, indicating the presence of the alpha 1 isoform. Protein kinase C and cAMP-dependent protein kinase phosphorylated Na+,K(+)-ATPase alpha subunit in DS and DR rats, and the phosphorylation by protein kinase C was associated with an inhibition of enzyme activity. The kinetic parameters for K+ activation were also studied in a preparation of basolateral membranes and were found to be similar in DS and DR rats. In a preparation of cortical tubule cells, Na+,K(+)-ATPase activity was determined as ouabain-sensitive oxygen consumption (OS QO2). Maximal OS QO2, measured in Na+ loaded cells, was the same in DS and DR rats. The K0.5 for K+ was significantly lower in DS than DR rats (0.163 +/- 0.042 vs. 0.447 +/- 0.061 mM, P < 0.05), indicating that factors regulating Na+,K(+)-ATPase activity in intact cells are altered in DS rats. Kinetic parameters for Na+ activation in cells were the same in both strains. In summary, the function of renal Na+,K(+)-ATPase molecule is not altered in DS rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal Na+,K(+)-ATPase in Dahl salt-sensitive rats: K+ dependence, effect of cell environment and protein kinases. 831 Aug 42

It is proposed that an intracellular cycle exists to limit or terminate the insulin signal. The cycle involves increased synthesis of sn-1,2-diacylglycerol (DAG) in response to insulin. The DAG activates protein kinase C (PKC) which phosphorylates glycogen synthase either directly or through other protein kinases to render it inactive. Protein kinase C may also inhibit the insulin receptor by phosphorylation of receptor serine residues. Insulin resistance could then arise as a consequence of a persistent increase in DAG levels. Such an increase could occur in three different ways. Chronic hyperinsulinaemia could increase DAG levels by de-novo synthesis from phosphatidic acid, by hydrolysis of phosphatidylcholine, or by hydrolysis of glycosyl-phosphatidylinositol; DAG is also formed by hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2). This reaction, known as the 'PI response,' may be the connection between hypertension and insulin resistance. A third mechanism for an increase in DAG involves neural abnormalities. Thus, muscle denervation in the rat is characterized both by a profound insulin resistance and a large increase in DAG. It is possible that a similar increase occurs in humans and may explain the association between denervation, inactivity, and insulin resistance.
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PMID:Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance? 840 36

The modern diet is greatly different from that of our paleolithic forebears' in a number of respects. There is reason to believe that many of these dietary shifts can up-regulate intracellular signalling pathways mediated by free intracellular calcium and protein kinase C, particularly in vascular smooth muscle cells; this disorder of intracellular regulation is given the name 'PKC syndrome'. PKC syndrome may entail either a constitutive activation of these pathways, or a sensitization to activation by various agonists. The modern dietary perturbations which tend to induce PKC syndrome may include increased dietary fat and sodium, and decreased intakes of omega-3 fats, potassium, calcium, magnesium and chromium. Insulin resistance may be both a cause and effect of PKC syndrome, and weight reduction and aerobic training should act to combat this disorder. PKC syndrome sensitizes vascular smooth muscle cells to both vasoconstrictors and growth factors, and thus promotes both hypertension and atherogenesis. In platelets, it induces hyperaggregability, while in the microvasculature it may be a mediator of diabetic microangiopathy. In vascular endothelium, intimal macrophages, and hepatocytes, increased protein kinase C activity can be expected to increase cardiovascular risk. Up-regulation of protein kinase C in stem cells may also play a role in the promotion of 'Western' fat-related cancers. Practical guidelines for combatting PKC syndrome are suggested.
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PMID:Up-regulation of intracellular signalling pathways may play a central pathogenic role in hypertension, atherogenesis, insulin resistance, and cancer promotion--the 'PKC syndrome'. 867 54

Hyperglycemia is believed to be a major cause of diabetic vascular complications. To elucidate the effect of hyperglycemia on vascular response, we studied hyperproliferation, hypertrophy, and the natriuretic peptide response of vascular smooth muscle cells under high-glucose conditions. We observed that cells cultured in high glucose (22.2 mmol/L) showed hyper-proliferation and hypertrophy and that natriuretic peptide receptor responses were suppressed compared with cells cultured in normal glucose (5.6 mmol/L). We also examined phospholipase D and protein kinase C activities and found that in high-glucose conditions such activities are higher than in cells cultured in normal glucose. The activation of phospholipase D was not prevented by coincubation with 1 mumol/L protein kinase C(19-36), a specific protein kinase C inhibitor, but the activation of protein kinase C was. Protein kinase C(19-36) also markedly attenuated vascular hyperproliferation and hypertrophy as well as glucose-induced suppression of natriuretic peptide receptor response. These results show that hyperglycemia may be linked to vascular hyperproliferation, hypertrophy, and a suppressed natriuretic peptide receptor response, which are caused by increased phospholipase D and protein kinase C activities.
Hypertension 1996 Aug
PMID:Possible involvement of phospholipase D and protein kinase C in vascular growth induced by elevated glucose concentration. 870 76

We measured Na(+)-H+ exchange as the amiloride-inhibited fraction of H+ efflux from red blood cells into a sodium-containing medium (pHo 7.95 to 8.05) at pHi values of 6.05 to 6.15, 6.35 to 6.45, 6.95 to 7.05, and 7.35 to 7.45 in 12 drug-free patients with primary aldosteronism before and after excision of histologically proven aldosterone-producing adrenal adenoma, 12 drug-free essential hypertensive patients, and 12 healthy control subjects. Red blood cell Na(+)-H+ exchange was increased in patients with primary aldosteronism similarly to the mean exchanger velocity in essential hypertensive patients compared with values in healthy subjects (334 +/- 25 and 310 +/- 29 versus 139 +/- 21 mumol H+/L cells per minute, respectively; P < .001 and .01). The kinetic parameters of Na(+)-H+ exchange returned to normal on day 2 after removal of the aldosterone-producing mass. Km for [Na+]o was not affected by aldosterone, whereas Km for [H+]i was decreased in patients with primary aldosteronism. The kinetic characteristics did not differ in essential hypertensive patients and control subjects. Protein kinase C inhibition in vitro by calphostin C (60 nmol/L) increased Km for [H+]i and caused up to a 65% suppression of Na(+)-H+ exchange (pHi 6.05 to 6.15). while diminishing Km for [Na+]o in red blood cells of patients with primary aldosteronism. The calmodulin antagonist W-13 (60 mmol/L) decreased exchanger velocity and increased Km for both H+ and Na+. We conclude that aldosterone stimulates red blood cell Na(+)-H+ exchange by a nongenomic mechanism that augments the exchanger affinity to Na+ and H+. In primary aldosteronism, protein kinase C and calmodulin seem to have synergistic stimulatory effects on red blood cell Na(+)-H+ exchange, and both increase the affinity of the exchanger to H+, while their effect on Na+ binding is opposite.
Hypertension 1997 Feb
PMID:Increased Na(+)-H+ exchange in red blood cells of patients with primary aldosteronism. 904 Apr 43

The clinical features of 106 patients of Takayasu arteritis (TA) seen over a period of 16 years are documented (65 females and 41 males). The mean age was 27.3 +/- 9.2 years. Hypertension was the commonest mode of presentation (51.3%) and was detected in 82 patients (77.4%) at the time of presentation. Vascular bruits were heard in 72 patients (67.9%) and 13 patients (12.3%) were in congestive heart failure. Aortography was performed in 95 patients. Based on the extent of involvement, Type I (branches of aortic arch) was seen in 7 (6.6%) patients, Type II (aortic arch, its branches and descending thoracic aorta) in 7 (6.6%) patients, Type III (descending thoracic aorta and abdominal aorta) in 4 (3.8%) patients, Type IV (abdominal aorta only) in 29 (27.3%) patients and Type V (aortic arch, descending thoracic aorta and abdominal aorta) in 59 (55.7%) patients. Therapeutic modalities included antihypertensive drug therapy in 81 patients, antitubercular drugs in 8 patients, steroids in 16 patients and cyclophosphamide in one patient. Response to steroids was satisfactory in 5 of these 16 patients while the lesions of vasculitis healed in the patient who was treated with cyclophosphamide. Surgical interventions included nephrectomy and autotransplantation of kidney in 3 patients each and revascularization in 4 patients and angioplasty in 4 patients. In the area of pathogenesis of this disease, a high activity of protein kinase C(PKC), an increased intracellular calcium and inositol 1,4,5 triphosphate in both unstimulated and stimulated T cells of TA was observed. These findings suggest an activation of PKC-calcium pathway in TA.
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PMID:Current status of Takayasu arteritis in India. 911 12

Increased activity of the Na(+)-H+ exchanger (NHE-1 isoform) has been observed in cells and tissues from hypertensive humans and animals, including the spontaneously hypertensive rat (SHR). No mutation in NHE-1 DNA sequence or alteration in NHE-1 mRNA and protein expression has been demonstrated in hypertension, indicating that alterations in proteins that regulate NHE-1 activity are responsible for increased activity. The recent finding that NHE-1 phosphorylation in SHR vascular smooth muscle cells (VSMCs) was greater than in Wistar-Kyoto rat (WKY) VSMCs suggested that NHE-1 kinases may represent an abnormal regulatory pathway present in hypertension. To define NHE-1 kinases altered in the hypertensive phenotype. We measured NHE-1 kinase activity by an in-gel-kinase assay using a recombinant glutathione S-transferase NHE-1 fusion protein as a substrate. At least 7 NHE-1 kinases (42 to 90 kD) were present in VSMCs. We studied a 90-kD kinase because it was the major NHE-1 kinase and exhibited differences between SHR and WKY. Comparison of 90-kD kinase activity revealed that SHR VSMCs had increased activity in growth-arrested cells and in cells stimulated by angiotensin II (100 nmol/L for 5 minutes). Activation of the 90-kD kinase by angiotensin II was Ca2+ dependent, PKC independent, and partially dependent on the mitogen-activated protein kinase pathway. These findings indicate that increased activity of a 90-kD NHE-1 kinase is a characteristic of SHR VSMCs in culture and suggest that alterations in the 90-kD NHE-1 kinase and/or proteins that regulate its activity may be a pathogenic component in hypertension in the SHR.
Hypertension 1997 Jun
PMID:A 90-kD Na(+)-H+ exchanger kinase has increased activity in spontaneously hypertensive rat vascular smooth muscle cells. 918 Jun 27

This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-mineralocorticoid receptors and the enzyme 11 beta hyderoxysteroid dehydrogenase-will be given as background. Next is a brief consideration of the three single-gene causes of human hypertension described to date-glucocorticoid-remediable aldosteronism. Liddle's syndrome, and apparent mineralocorticoid excess-in all of which abnormal sodium handling is a feature. Third, the sequelae of aldosterone occupancy of nonepithelial mineralocorticoid receptors will be analyzed in some detail by reviewing studies on experimental mineralocorticoid hypertension and cardiac fibrosis from this laboratory and elsewhere. Finally, three recent studies from this laboratory will be presented: on putative 11-ketosteroid receptors in epithelial tissue, on glucose-PKC potentiation of mineralocorticoid effects on heart cells, and on the necessity for factors/ processes other than the conversion of cortisol to cortisone (or, in the rat, corticosterone to 11-dehydrocorticosterone) to ensure aldosterone-specific effects in mineralocorticoid target tissues.
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PMID:Mineralocorticoid receptors, salt, and hypertension. 923 55

The classical effects of aldosterone are mediated via epithelial mineralocorticoid receptors (MR), protected against cortisol/corticosterone occupancy and activation by the enzyme 11 beta hydroxysteroid dehydrogenase. The pathophysiological effects of aldosterone on non-epithelial tissues, in contrast, are mediated via unprotected MR in which occupancy by cortisol/corticosterone antagonises the effect of aldosterone. Aldosterone raises blood pressure by occupying MR in the circumventricular region of the brain, an effect antagonised by concomitant intracerebroventricular (ICV) infusion of similar doses of corticosterone. Peripheral infusion of aldosterone to salt loaded rats causes hypertension, cardiac hypertrophy and cardiac fibrosis; concomitant ICV infusion of the MR antagonist RU28318 abolishes the aldosterone-induced hypertension, but does not affect cardiac hypertrophy or fibrosis. These peripheral effects of aldosterone are presumably via cardiac MR; high glucose/PKC modulated, aldosterone-specific effects on protein synthesis have recently been demonstrated as direct MR-mediated actions on cultured neonatal rat cardiomyocytes. The pathophysiologic effects of aldosterone via nonepithelial MR have a time course of days/weeks rather than hours, reflect occupancy of only a small percentage of such receptors, and require salt loading. How the effects of salt loading are transduced in such circumstances remains to be explored.
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PMID:Aldosterone, salt and cardiac fibrosis. 924 62


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