Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of insulin on Ca2+ regulation of vascular smooth muscle cells (VSMC) in hypertension, the effect of insulin on Ca2+ transport and intracellular free calcium concentration ([Ca2+]i) was measured in cultured VSMC from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Insulin produced a substantial increase in 45Ca uptake as well as [Ca2+]i in quiescent cultured VSMC. The stimulatory effects of insulin were completely inhibited by diltiazem, and partially by H-7, TMB-8, and 5-N,N(hexamethylene)amiloride (HMA), but not by W-7 or trifluoroperazine. Insulin-sensitive 45Ca uptake of SHR VSMC was significantly smaller than that of WKY VSMC. Insulin-sensitive increase in [Ca2+]i of SHR VSMC was also smaller than that of WKY VSMC. It is concluded that insulin increases 45Ca uptake, leading to an increase in [Ca2+]i, presumably through the voltage-dependent Ca2+ channel, intracellular Ca2+ release, or protein kinase C mediated mechanisms in cultured VSMC. A blunted response of insulin-sensitive Ca2+ uptake and [Ca2+]i in SHR VSMC suggests the differential regulation of Ca2+ transport in response to insulin in primary hypertension.
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PMID:Decreased insulin-sensitive Ca2+ transport in cultured vascular smooth muscle cells from spontaneously hypertensive rats. 128 39

There is evidence that the cytosolic free Ca2+, protein kinase C, and the Na(+)-H+ antiport cross-communicate with one another through positive and negative feedback mechanisms, thereby maintaining cellular Ca2+ and pH homeostasis. This triumvirate may play a role in the development of insulin resistance--a common characteristic of both essential hypertension and non-insulin-dependent diabetes mellitus. Circulating cells from patients with essential hypertension and non-insulin-dependent diabetes mellitus demonstrate elevated cytosolic free Ca2+, increased protein kinase C activity, or both, and these perturbations are associated with augmented activity of the Na(+)-H+ antiport. If present in other cells (e.g., striated muscle cells and adipocytes), these alterations could underlie insulin resistance in essential hypertension and non-insulin-dependent diabetes mellitus.
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PMID:The roles of cell Ca2+, protein kinase C and the Na(+)-H+ antiport in the development of hypertension and insulin resistance. 133 4

Although abnormalities in cellular ion transport have been shown in a variety of cells of essential hypertensives, the mechanistic link between these abnormalities and elevated blood pressure is poorly understood. Reduced sodium-potassium ATPase activity, with and without elevated levels of a circulating inhibitor of this transport system, has been reported by a number of studies. The recent characterization of the endogenous ouabain or its isomer will facilitate the testing of the hypothesis that salt-sensitive essential hypertension relates to higher levels of this factor. The erythrocyte sodium-lithium countertransport may serve as a marker for a subpopulation of essential hypertensives. However, this transport system has no physiologic counterpart and thus does not provide insight into mechanisms associated with altered cellular ionic homeostasis in essential hypertension. Increased activity of the sodium-hydrogen antiport in essential hypertension relates to an alkaline shift in the cytosolic pH set-point for activation of this transport system. This process may reflect increased cytosolic free calcium concentration with or without augmented protein kinase C activity.
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PMID:Defects in membrane transport of ions as possible pathogenic factors in hypertension. 136 33

Platelet intracellular free calcium concentration [Ca2+]i from patients with essential hypertension has been found to be elevated, but the intracellular effects of this increase are still unclear. As protein phosphorylation is an important regulatory step in cell activation and increased protein phosphorylation has been demonstrated in platelets from hypertensive animals, we investigated protein phosphorylation and [Ca2+]i in platelets from patients with essential hypertension and age-matched normotensives. We measured the 32P incorporation into a 20 kDa protein and a 47 kDa protein in 17 hypertensive patients and 20 normotensive, age-matched subjects. The [Ca2+]i was measured with the fluorescent dye fura-2. Protein phosphorylation and [Ca2+]i were assessed in unstimulated platelets and after exposure of the cells to 0.1 and 0.25 U/mL thrombin at 20, 60, and 300 sec. In addition we assessed the activity of protein kinase C by incubating the platelets with phorbol-ester TPA at 20, 60, and 300 sec. Basal phosphorylation of the two proteins was not different between the two groups. After exposure of the platelets to thrombin 32P, incorporation into the 20 kDa protein and the 47 kDa protein was significantly increased in platelets from hypertensive patients at all times. Furthermore, the specific stimulation of protein kinase C with TPA resulted in a significantly higher phosphorylation of the 47 kDa protein, whereas the 20 kDa protein was not phosphorylated after incubation with TPA for 1 min. Basal [Ca2+]i was higher in platelets from hypertensive patients (124 +/- 7 nmol/L v 104 +/- 5 nmol/L, P less than .05), although there was a wide overlap between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein phosphorylation and intracellular free calcium in platelets of patients with essential hypertension. 157 40

Leucocyte Na+/H+ antiport activity is elevated in patients with essential hypertension and Type 1 diabetes with nephropathy. To examine the effects of hyperglycemia on the Na+/H+ antiport, normal leucocytes were incubated with 25 mmol l-1 D-glucose, L-glucose or glucose-6-phosphate for two days. Leucocyte Na+/H+ antiport activity was measured by a novel double ionophore fluorimetric method for controlling intracellular pH. Only incubation with D-glucose led to an increase in Na+/H+ antiport activity of about 31%. This effect was not due to non-enzymic glycation since glucose-6-phosphate, which glycates proteins faster than D-glucose, caused no significant difference in antiport activity. Also, osmotic effects could be excluded. Staurosporine (10 nmol l-1), a specific inhibitor of protein kinase C, prevented the rise in antiport activity due to incubation with D-glucose. As hyperglycaemia is known to increase protein kinase C activity, elevation of this kinase may be one mechanism for activation of the Na+/H+ antiport in Type 1 diabetes.
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PMID:Stimulation of the human leucocyte Na+/H+ antiport by D-glucose is mediated by protein kinase C. 166 30

In order to determine the mechanisms which could be responsible for the hypertrophy of vascular wall associated with primary hypertension, we have investigated the mechanisms involved in the proliferation of aortic cells from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls. In this study we have examined the role of phospholipase C which is responsible for the formation of second messengers, the function of protein kinase C and that of GTP-binding proteins (G proteins) which couple membrane receptors to phospholipase C. The adventitial fibroblasts from thoracic aorta were chosen as cell model in culture. The capacity of proliferation in response to 10% serum was analyzed by cell number determination and by measuring the incorporation of 3H-thymidine into newly synthesized DNA. Our results showed that SHR-derived fibroblasts proliferated more rapidly and incorporated more 3H-thymidine than WKY-derived fibroblasts. However, the phospholipase C activity, measured by the serum-stimulated production of 3H-inositol phosphates in cells prelabeled with 3H-inositol, did not differ between SHR- and WKY-derived cells. The desensitization of protein kinase C, by long term (2 d) treatment with high dose (300 nM) of phorbol 12-myristate, 13-acetate (TPA), markedly augmented, but to the same extent, the 3H-thymidine incorporation into DNA of SHR- and WKY-derived fibroblasts. Moreover, protein kinase C activation by TPA caused a parallel reduction (25-30%) of the incorporation of 3H-thymidine into DNA of SHR- and WKY-derived cells. Under the same experimental conditions, the growth of SHR- and WKY-derived fibroblasts was reduced by TPA in a dose-dependent manner (up to 20%) to the same extent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Study of mechanisms responsible for hyperproliferation of aortic cells in spontaneously hypertensive rats]. 195 50

To gain insight into the mechanisms that could account for the augmentation of cellular reactivity in primary hypertension, we have examined some of the biochemical events which are implicated in the transmission of mitogenic signal as well as in cell reactivity. This study focussed on phospholipase C, protein kinase C and GTP-binding proteins (G-proteins), in response to thrombin or arginin-vasopressin (AVP). Cultured fibroblasts prepared from the adventitia of thoracic aorta of spontaneously hypertensive rat (SHR) were used as cell models and were compared with fibroblasts prepared from controls Wistar-Kyoto (WKY) rats. The mitogenicity of each agonist was estimated by measuring the incorporation of 3H-thymidine into the newly synthesized DNA. The agonist-induced phospholipase C activity was evaluated by measuring the production of 3H-inositol phosphates in cells prelabeled with 3H-inositol. The influence of protein kinase C and that of G proteins on the mitogenesis in cells stimulated by thrombin or AVP was determined by pretreating cells with phorbol 12-myristate, 13-acetate (TPA) and pertussis toxin, respectively. Kinetics and dose response studies have demonstrated that in response to thrombin and AVP, the phospholipase C activity and the incorporation of 3H-thymidine were significantly higher in the fibroblasts derived from SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Activation mechanisms by thrombin and vasopressin of fibroblasts in spontaneously hypertensive rats]. 195 75

The rate of delta mu H+ --induced erythrocyte Na+/H+ exchange is increased in both patients with essential hypertension (EH) and spontaneously hypertensive rats (SHR). The increase of Na+,K(+)-cotransport was revealed in erythrocytes of SHR only. This alteration as well as a decrease of mean cell volume were observed in both young and old erythrocytes of SHR. The moderate shrinkage of rat (but not human) erythrocytes results in an increase of the rate of Na+,K(+)-cotransport. The more pronounced shrinkage of rat (but not human) erythrocytes induces the Na+/H+ exchange. These reactions are accompanied by phosphoinositide response. Activator of protein kinase C (TPA) increases delta mu H+ --induced Na+/H+ exchange both in human and rat erythrocytes but it does not modify phosphoinositide metabolism. No differences were observed in the rate of Na+/H+ exchange between TPA-treated erythrocytes of SHR and WKY. We assume that the activation of protein kinase C increases Na+/H+ exchange in primary hypertension. Increased Na+/H(+)-cotransport revealed in an experimental model of primary hypertension is probably due to the decrease of erythrocyte volume.
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PMID:Volume-dependent regulation of cation transport and polyphosphoinositide metabolism in human and rat erythrocytes: features revealed in primary hypertension. 216 66

Protein kinase C activity in the lysate of erythrocytes of patients with essential hypertension (EH) and spontaneously hypertensive rats (SHR) was found to be increased by 1.6-2.0 times as compared with normotensive controls. Membrane cytoskeleton alterations observed in the erythrocytes of patients with EH and SHR were revealed in decreased average erythrocyte volume, increase of cup-shaped cell formation, and increase of basal phosphorylation of band 4.9 protein. In addition, the rate of Na(+)-H+ exchange in erythrocytes of EH patients and SHR was increased by 1.9-fold. In vitro treatment of erythrocytes of healthy donors and Wistar-Kyoto rats (WKY) with protein kinase C activator (12-O-tetradecanoylphorbol-13-acetate) leads to similar changes of cell shape, cell volume, band 4.9 protein phosphorylation and Na(+)-H+ exchange, as well as to an increase of diS-C3-(5) fluorescence. It may be assumed that alterations of these parameters revealed in primary hypertension are caused by increased activity of protein kinase C.
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PMID:Protein kinase C activity in erythrocytes in primary hypertension: regulation of cell shape and cation transport. 216 67

It is uncertain why only one third of Type 1 (insulin-dependent) diabetic patients develop nephropathy. One suggestion is the inheritance of a predisposition to essential hypertension. We have previously found elevated Na+/H+ antiport activity and a raised intracellular pH in leucocytes from hypertensive and Type 1 diabetic subjects with albuminuria using a novel double ionophore fluorimetric technique. These changes are not found in Type 1 diabetic subjects without albuminuria. We wished to test the effect of a protein kinase C inhibitor staurosporine (100 nmol/l) on the elevated antiport activity, and the degree of stimulation achieved by exogenous diacyl glycerol. Raised leucocyte Na+/H+ antiport activity of Type 1 diabetic subjects with albuminuria (73.8 +/- 17.2 mmol.l-1.min-1) was restored to normal levels with staurosporine (54.9 +/- 17.9 mmol.l-1.min-1, p less than 0.001). The leucocyte Na+/H+ antiport activity of diabetic subjects without albuminuria fell significantly also with staurosporine but to a lesser extent (57.3 +/- 11.6 to 50.0 +/- 12.8 mmol/l, p less than 0.003). In contrast, leucocytes from normal control subjects showed no change in antiport activity with staurosporine (54.3 +/- 8.5 to 52.6 +/- 10.4 mmol.l-1.min-1). Dioctanoyl glycerol stimulated the leucocyte Na+/H+ antiport in normal subjects and diabetic patients without albuminuria, with significantly less stimulation in diabetic patients with albuminuria. We conclude that reversal by staurosporine of the elevated Na+/H+ antiport activity in Type 1 diabetic subjects with albuminuria could indicate a role for protein kinase C in activating the antiport. This hypothesis is supported by the reduced stimulation of the antiport by dioctanoyl glycerol in this group of patients.
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PMID:Effect of protein kinase C modulators on the leucocyte Na+/H+ antiport in type 1 (insulin-dependent) diabetic subjects with albuminuria. 165 56


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