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)

In this study we used endothelin as a paradigm to explore the concept that some vasoactive agents, acting through mobilization of Ca2+ and stimulation of protein kinase C, can interact with human skeletal muscle and modify its glucose transport. Cultured human skeletal myoblasts from the vastus lateralis demonstrated two subclasses of high-affinity endothelin receptors and a robust increase in cytosolic free Ca2+ upon exposure to endothelin. The endothelin-evoked rise in cytosolic free Ca2+ primarily resulted from Ca2+ mobilization from intracellular organelles. Both endothelin and insulin enhanced [3H]deoxy-D-glucose uptake in human myoblasts, but their effects were not additive. These findings also were observed in differentiated myotubes of L6 skeletal muscle cells. Moreover, [3H]deoxy-D-glucose uptake in human myoblasts was enhanced by treatment with phorbol 12-myristate 13-acetate. The endothelin- and insulin-mediated increases in [3H]deoxy-D-glucose were totally ablated by treatment with calphostin C. Such observations suggest that endothelin can enhance glucose uptake in human skeletal muscle. This is mediated through mechanisms that are at least partially protein kinase C dependent. Thus, increased levels of endothelin in vascular beds may contribute to altered glucose metabolism in essential hypertension.
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PMID:Endothelin mobilizes calcium and enhances glucose uptake in cultured human skeletal myoblasts and L6 myotubes. 751 52

The relationships among the cytosolic free Ca2+ (Cai), protein kinase C (PKC), and the Na+/H+ antiport may hold the key to unraveling the causes and origin of essential hypertension. Increased cellular Ca2+, accelerated Cai turnover rate, or both occur in concert with activation of PKC and the Na+/H+ antiport in a variety of cells. In the vascular smooth muscle cell a rise in Cai produces increased tone and in the kidney it enhances sodium retention through stimulation of the Na+/H+ antiport in the renal tubules. In skeletal muscle increased Cai and augmented PKC activity produces insulin resistance, which is a major characteristic of essential hypertension. Moreover, elevation of Cai, in conjunction with increased activities of PKC and the Na+/H+ antiport, may exert trophic effects on the vasculature and the heart, thereby explaining the narrowing of the vascular lumen in peripheral arteries and the cardiac hypertrophy of long-standing hypertension. Because essential hypertension is a common disorder, its evolutionary advantage in primeval times could rest in skeletal muscle, where higher Ca2+ stores and increased Na+/H+ antiport activity enhanced muscular performance and provided a crucial survival element.
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PMID:Cytosolic Ca2+, Na+/H+ antiport, protein kinase C trio in essential hypertension. 817 56

The different effects of cytokines on cytosolic-free calcium concentration ([Ca2+]i) and intracellular stored calcium were investigated in platelets from 35 essential hypertensive patients (HT) and 45 age- and sex-matched normotensive control subjects (NT). Erythropoietin (EPO) and interleukin 2 significantly increased platelet [Ca2+]i, whereas platelet-derived growth factor, and fibroblast growth factor had no significant effect on [Ca2+]i. The EPO-induced rise of [Ca2+]i was significantly higher in HT compared to NT (15.2 +/- 4.3 nmol/L v 1.3 +/- 1.7 nmol/L, P < .01). Preincubation with EPO significantly increased calcium in intracellular stores in platelets from HT and NT. Inhibition of protein kinase C significantly enhanced EPO-induced rise of stored calcium. It is concluded that an increased response of HT to EPO may be associated with essential hypertension.
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PMID:Effect of cytokines on cytosolic-free calcium in human platelets from essential hypertensives. 821 28

Brain angiotensin II (Ang II) plays a key role in blood pressure control in part by interacting with catecholamines (CA) and by stimulation of sympathetic pathways. The significance of Ang-CA interaction is further heightened by the presence of a hyperactive brain Ang II system in spontaneously hypertensive (SH) rat, a genetic model for essential hypertension. Neuronal cells in primary culture from the hypothalamus-brainstem that mimic in vivo situations in so far as many cellular actions of Ang II are concerned, have been used in the present study to elucidate Ang II regulation of CA by determining its cellular action on the norepinephrine transporter (NET) system. Ang II causes both acute and chronic stimulation of [3H]-norepinephrine (NE) uptake in neuronal cultures of Wistar Kyoto (WKY) rat brain. Acute stimulation begins as early as 5 min, reaches maximal levels in about 30 min in the presence of 100 nM Ang II, and is blocked by losartan, a specific antagonist for AT1 receptor subtype. In addition, this acute stimulation appears to be a posttranscriptional event and does not involve protein kinase C (PKC) or NET gene transcription. Chronic stimulation of [3H]-NE uptake by Ang II persists throughout the duration of Ang II incubation (24 h), is dose dependent, and is also mediated by AT1 receptor subtype. However, chronic stimulation of [3H]-NE uptake involves PKC, cfos, and NET gene transcription. Ang II also stimulates [3H]-NE uptake in neuronal cultures of SH rat brain, both acutely and chronically, by mechanisms similar to those observed in neuronal cultures of WKY rat brain. The stimulation of NET by Ang II is 2-fold higher than that seen in WKY and is consistent with increased AT1 receptor gene transcription and increased functional AT1 receptors in SH rat brain neurons compared with WKY rat brain neurons. The Ang II stimulation of the NET system is also higher in adult SH compared with WKY rats in vivo. These observations show that 1) Ang II stimulates the NET system both acutely and chronically, the former involving activation of preexisting transporters and the latter involving NET gene transcription and translation; and 2) Ang II stimulation of the NET system is elevated in SH rat brain neurons.
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PMID:Regulation of norepinephrine transport system by angiotensin II in neuronal cultures of normotensive and spontaneously hypertensive rat brains. 859 28

1. In primary hypertension, an abnormally high vascular resistance can be explained in terms of alterations in vessel wall structure. Arterial cell hypertrophy and/or hyperplasia have been implicated as playing a central role in the vascular abnormalities noted in spontaneously hypertensive rats (SHR). Cultured arterial cells appear therefore as attractive models for studying in vitro the mechanisms whereby cells originating from hypertensives exhibit hyperproliferation and/or hyperresponsiveness. 2. This review summarized our present knowledge on growth and related biochemical events of cultured SHR-derived vascular smooth muscle cells or aortic adventitial fibroblasts, in response to various polypeptide growth factors and vasoactive agents. 3. Exaggerated growth response to various mitogens in cultured SHR-derived vascular cells has been well documented. However, the molecular mechanisms of abnormal growth in SHR remain unknown. This abnormality seems not to be a consequence of the alterations at the levels of receptors or of some key mitogenic events of early signalling pathways such as phospholipase C, protein kinase C and G-proteins. Further studies should therefore focus on the more distal events related to cell growth.
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PMID:Molecular mechanisms of vascular hypertrophy in the spontaneously hypertensive rat. 907 18

Na+/H+ exchange (NHE) was measured as maximal initial velocity of pH-dependent H+ efflux from red cells into an alkaline medium containing Na+ in patients with insulin-dependent or noninsulin-dependent diabetes, with and without hypertension and in normoglycemic, essential hypertensives and normal controls (50 subjects in each subgroup). Maximal velocities of NHE were found in microalbuminuric patients in all subgroups, and NHE correlated with the rate of micro-albuminuria (r = 0.61, p = 0.02). Daily insulin requirements were greater in those with elevated NHE (84 +/- 8 vs 42 +/- 4 U/day). There was no correlation between NHE and levels of plasma glucose, HbA1 and plasma aldosterone and lipid profile and PRA. NHE was correlated with plasma prolactin (r = 0.51, p = 0.02) and PTH r = 0.24, p = 0.05). In uremic patients, NHE was inversely correlated with creatinine clearance (r = -0.48, p = 0.03). Since calphostin C, a selective inhibitor of protein kinase C, lowered increased NHE in vitro, the protein kinase C-dependent pathway of the exchanger regulation was concluded to be responsible for NHE activation in diabetes mellitus and essential hypertension.
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PMID:[Red cell Na+/H+ exchange and role of protein kinase C in its stimulation in diabetes mellitus, essential hypertension and nephropathy]. 922 70

Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT1 receptor-mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti-human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT1 receptor. Peptides corresponding to sites on the AT1 receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT1 receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT1 receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II-induced vascular lesions in these patients.
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PMID:Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. 1019 66

Essential hypertension is characterized by significant and persistent elevations in arterial pressure. Hypertension is a multifactorial disorder that may involve abnormalities in the functions of the heart pump, the blood vessels, and the kidneys. Short-term and long-term regulation of arterial pressure is influenced by changes in cardiac function, the peripheral vascular resistance, and the renal control mechanisms of plasma electrolytes and volume. Increases in the heart rate and stroke volume lead to increases in the cardiac output and could contribute to increases in arterial pressure particularly in relatively young individuals. Vascular endothelial cell dysfunction could lead to reduction in endothelium-derived relaxing factors such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor, or increased production of contracting factors such as endothelin-1 and thromboxane A2. Also, increased activity of signaling pathways of vascular smooth muscle contraction such as [Ca(2+)]i, protein kinase C, mitogen-activated protein kinase, and Rho kinase could enhance vasoconstriction. The decreased vascular relaxation and excessive vasoconstriction lead to significant increases in the peripheral vascular resistance and arterial pressure over time, particularly with aging. Alterations in body fluid regulation by the kidneys could lead to salt and water retention, increased plasma volume, and cardiac output. Also, activation of the renin-angiotensin system increases the levels of angiotensin II in the plasma, leading to generalized vasoconstriction, or locally in the kidneys, leading to salt and water retention. Individual changes in cardiac, vascular, or renal function seldom occur separately, and, if so, they may lead to mild or moderate increases in arterial pressure. Combined alterations in cardiac, vascular, and renal functions are more common and are often associated with pathologic increases in arterial pressure and established hypertension.
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PMID:Pathophysiology of essential hypertension: role of the pump, the vessel, and the kidney. 1178 64

The studies concerning the structure and variations of the human adrenomedullin (AM) gene are reviewed, and their relations to the gene function and genetic predisposition to cardiovascular diseases are discussed. The genomic human AM gene is composed of four exons, and the whole nucleotide sequence corresponding to mature AM resides in the fourth exon. In chromosomal sublocalization, the AM gene is located in the distal portion of the short arm of chromosome 11 (11p15.1-3). Analysis of the promoter region of the AM gene has revealed that two transcription factors, nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2), participate in the regulation of AM gene expression. It is surmised that NF-IL6 mediates inflammatory stimuli and AP-2 mediates signals of phospholipase C and protein kinase C activation. In addition to these factors, hypoxia induces AM gene expression via the hypoxia inducible factor-1 (HIF-1) binding site. The 3'-end of the AM gene is flanked by a microsatellite marker of cytosine adenine (CA) repeats. In Japanese, there are four types of alleles with different CA-repeat numbers: 11, 13, 14 and 19. It is suggested that existence of the 19-repeat allele is associated with genetic predispositions to develop essential hypertension and diabetic nephropathy.
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PMID:Variations of human adrenomedullin gene and its relation to cardiovascular diseases. 1263 Aug 23

Recent studies demonstrate low serum levels of 25-hydroxyvitamin D in patients with congestive heart failure (CHF). Although this may in part reflect reduced capacity for outdoor exercise, the possibility that poor vitamin D status increases risk for left ventricular hypertrophy (LVH), and its common sequel CHF, merits consideration. In cardiomyocytes, hormones which activate protein kinase C (PKC) -- including norepinephrine, angiotensin II, and endostatin, implicated in the pathogenesis of LVH -- induce a hypertrophic response analogous to that seen in LVH. Transgenic mice overexpressing PKC-beta2 or its upstream activator Galphaq in cardiac myofibers develop a syndrome similar to LVH. Parathyroid hormone (PTH) also activates Galphaq and PKC in cardiomyocytes, and provokes the expected hypertrophic response. Both primary and secondary hyperparathyroidism are associated with high risk for LVH. Moreover, in uncomplicated essential hypertension, left ventricular mass index has been shown to correlate very tightly with serum PTH levels, independent of blood pressure. This latter finding suggests that variations of PTH within the normal range can influence induction of LVH in at-risk subjects. If so, nutritional and lifestyle measures which modulate PTH secretion may have an impact on LVH risk. PTH secretion should be down-regulated by good vitamin D status -- achieved through supplementation or regular uv exposure -- and by vegan diets moderately low in bioavailable phosphate. Although high calcium intakes can likewise suppress PTH, they also boost renin secretion, which could have a countervailing effect on risk for LVH. Whether these nutritional measures do indeed influence LVH risk could be examined in prospective studies targeting patients at high risk, such as hypertensives.
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PMID:Nutritional modulation of parathyroid hormone secretion may influence risk for left ventricular hypertrophy. 1578 May 3


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