Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several recent studies indicate that type 2 diabetes, arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors which might belong to a syndrome which is caused by decreased insulin sensitivity with compensatory hyperinsulinaemia. More than 50% of patients with essential hypertension have some degree of insulin resistance, but in contrast to dyslipoproteinaemia and glucose intolerance the causal relation between insulin resistance and elevated arterial blood pressure appears not to be as evident. One explanation is that the link between blood pressure and insulin sensitivity might be mainly related to concomitant obesity. Accordingly, obesity can be associated with an increased activity of the sympathetic nervous system, elevated plasma levels of the vasoconstrictor endothelin-1, and decreased insulin-induced endothelium-dependent vasodilation. Furthermore, adipocytes can secrete vasogenic peptides, such as angiotensinogen. Since insulin resistance is a polygenic disorder, the two basic genetic approaches we follow is to identify genetic defects of insulin action in cells of patients with inherited syndromes of insulin resistance and to characterize molecular mechanisms of insulin regulated gene expression. The results show that insulin can affect the expression rate of various genes, e.g. involved in cholesterol and fatty acid metabolism, by modulating the activity of transcription factors coupled to the MAP kinase cascade and that a genetic postreceptor defect in these intracellular signaling pathways might have a pleiotropic effect on cell metabolism and clinical phenotype.
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PMID:Metabolic syndrome and hypertension: pathophysiology and molecular basis of insulin resistance. 983 75

The mitogen-activated protein (MAP) kinase family members are ubiquitously expressed protein kinases activated in response to a variety of extracellular stimuli and shown to be involved in cell growth, transformation, differentiation and apoptosis. MAP kinases have been implicated in both growth and apoptosis of vascular smooth muscle cells (VSMC) which suggests that they play important roles in cardiovascular diseases such as essential hypertension, atherosclerosis, and restenosis followed angioplasty. The MAP kinases are themselves components of specific kinase cascades characterized by activation by specific stimuli, families of related serine and threonine kinases and downstream substrates that include other kinases, transcription factors, membrane receptors and other cell mediators. Cross-talk among the different MAP kinases results in direct modulation of signal transduction. In addition, increased expression and activation of MAP kinase phosphatases plays an important role in MAP kinase inactivation. Our laboratory has used angiotensin II (AngII), a potent activator of all MAP kinases in VSMC, to study mechanisms by which MAP kinases are regulated by vasoactive peptides. In this review, we describe the mechanisms by which AngII activates MAP kinases, and potential roles for MAP kinases in AngII-dependent effects on VSMC function.
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PMID:MAP kinases and vascular smooth muscle function. 988 83

alpha(2A)-Adrenergic receptors (alpha(2A)AR) are presynaptic autoinhibitory receptors of noradrenergic neurons in the central and peripheral sympathetic nervous systems, which act to dynamically regulate neurotransmitter release. Signaling through the G(i)/G(o) family of G-proteins, the receptor subserves numerous homeostatic and central nervous system functions. A single nucleotide polymorphism of this receptor, which results in an Asn to Lys substitution at amino acid 251 of the third intracellular loop, was identified in the human population. The frequency of Lys-251 was 10-fold greater in African-Americans than in Caucasians, but was not associated with essential hypertension. To determine the consequences of this substitution, wild-type and Lys-251 receptors were expressed in CHO and COS-7 cells. Expression, ligand binding, and basal receptor function were unaffected by the substitution. However, agonist-promoted [(35)S]GTPgammaS binding was approximately 40% greater with the Lys-251 receptor. This enhanced agonist function was observed with catecholamines, azepines, and imidazolines albeit to different degrees. In studies of agonist-promoted functional coupling to G(i), the polymorphic receptor displayed enhanced inhibition of adenylyl cyclase (60 +/- 4. 4 versus 46 +/- 4.1% inhibition) and markedly enhanced stimulation of MAP kinase (57 +/- 9 versus 15- +/- 2-fold increase over basal) compared with wild-type alpha(2A)AR. The potency of epinephrine in stimulating inositol phosphate accumulation was increased approximately 4 fold with the Lys-251 receptor. Unlike previously described variants of G-protein-coupled receptors, where the minor species causes either a loss of function or increased non-agonist function, Lys-251 alpha(2A)AR represents a new class of polymorphism whose phenotype is a gain of agonist-promoted function.
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PMID:An asn to lys polymorphism in the third intracellular loop of the human alpha 2A-adrenergic receptor imparts enhanced agonist-promoted Gi coupling. 1094 91

Abnormal vascular smooth muscle cell proliferation has a fundamental role in the pathogenesis of vascular diseases. Indapamide is an oral diuretic antihypertensive drug effective for patients with mild or moderate essential hypertension. We now investigated the effects of indapamide on the growth of aortic vascular smooth muscle cells (A10 cell line). Indapamide inhibited cell proliferation as measured by the tetrazolium salt XTT (sodium 3'-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate) test. The increase in cell number was significantly reduced in the presence of indapamide 10(-6) and 5 x 10(-4) M (P < 0.05 n = 3 and P < 0.01, n = 3, respectively). Serum-induced DNA synthesis, determined as the incorporation of 5-bromo-2'-deoxyuridine (BrdU), was concentration-dependently inhibited by indapamide. BrdU incorporation was 47.2+/-1.6% (10% foetal calf serum). Indapamide treatment markedly prevented BrdU incorporation (37.2+/-2.1%, 29.2+/-4.8%, 15.0+/-1.8%, 8.7+/-2.1%) indapamide 10(-6), 10(-5), 5 x 10(-5) and 5 x 10(-4) M, respectively. Cell-cycle progression was also evaluated. Flow cytometry analysis of DNA content in synchronised cells revealed blocking of the serum-inducible cell-cycle progression by indapamide. This inhibition was abolished when the drug was added 2 h after serum repletion, indicating that indapamide must act at the early events of a cell cycle to be fully effective against DNA synthesis. In addition, serum-induced intracellular Ca2+ movements and also p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation were studied in the presence or absence of indapamide. Indapamide 10(-5) and 5 x 10(-5) M decreased significantly cytosolic free calcium, and the p44/p42 mitogen-activated protein kinase phosphorylation (5 x 10(-5) M) stimulated by 10% foetal calf serum. In accordance with this finding, indapamide (5 x 10(-4) M) caused a 95% to 99% decrease in the early elevation of c-fos expression as evaluated by northern blot analysis of mRNA induced after serum addition. In conclusion, our results indicate that indapamide reduces vascular smooth muscle cell proliferation by a mechanism which involves a decrease in the intracellular Ca2+ movements that might link with the mitogen-activated protein kinase (MAPK) pathway, altering cell-cycle progression.
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PMID:Growth inhibitory activity of indapamide on vascular smooth muscle cells. 1177 33

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

Endothelin-1 (ET-1) and oxidized low-density lipoprotein (ox-LDL) are associated with atherosclerosis and essential hypertension. We assessed the effect of mildly oxidized LDL (mox-LDL) and ox-LDL and their major oxidative components, i.e., reactive oxygen species (ROS), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) and their interaction with ET-1 on vascular smooth muscle cell (VSMC) proliferation. Growth-arrested VSMCs isolated from the rabbit aorta were incubated with different concentrations of LDL, mox-LDL, ox-LDL, hydrogen peroxide (H(2)O(2)) (a donor of ROS), LPC, or HNE with or without ET-1. DNA synthesis in VSMCs was measured by [(3)H] thymidine incorporation. Mox-LDL, ox-LDL, H(2)O(2), LPC, HNE, or ET-1 stimulated DNA synthesis in a dose-dependent manner. Maximal effect was observed at 5 microg/ml for mox-LDL (162%) or ox-LDL (154%), 15 microM LPC (156%), 5 microM H2O2 (177%), 1 microM HNE (144%), and 0.1 microM ET-1 (195%). By contrast, LDL was without any significant effect. When added together, there was no synergistic effect of LDL, H2O2, or HNE with ET-1 on DNA synthesis. However, the effect of mox-LDL (0.1 microg/ml), ox-LDL (0.5 microg/ml), or LPC (10 microM) was potentiated by ET-1 (114%-338%, 133%-425%, 118%-333%, respectively). The mitogenic effect of mox-LDL, ox-LDL, or LPC and their interaction with ET-1 were inhibited by defatted albumin (10 microg/ml), antioxidant N-acetylcysteine (400 microM), the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (1 microM). The ET(A/B) receptor antagonist TAK044 (1 microM) or the MAPK kinase inhibitor PD098059 (10 microM) inhibited the mitogenic effect of ET-1 and its interaction with mox-LDL, ox-LDL, or LPC. The synergistic interaction of mox-LDL, ox-LDL, or LPC with ET-1 was completely reversed by the combined use of N-acetylcysteine and TAK044. Our results suggest that mox-LDL, ox-LDL, and their major phospholipid component LPC act synergistically with ET-1 in inducing VSMC proliferation by way of the activation of redox-sensitive and MAPK pathways.
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PMID:Lysophosphatidylcholine is a major contributor to the synergistic effect of mildly oxidized low-density lipoprotein with endothelin-1 on vascular smooth muscle cell proliferation. 1186 25

Hypertension that results in left ventricular (LV) hypertrophy and/or fibrosis can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. To investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, an adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar-Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 wk, but had no effect from 3 to 5 wk. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV-to-heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes after kallikrein gene transfer were associated with decreases in JNK activation as well as transforming growth factor (TGF)-beta 1 and plasminogen activator inhibitor-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-beta 1, and plasminogen activator inhibitor-1 via the nitric oxide-cGMP pathway.
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PMID:Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats. 1281 55

As in essential hypertension, chronic nitric-oxide synthase (NOS) inhibition leads to hypertrophic remodeling in conduit and muscular arteries and inward eutrophic remodeling in small resistance arteries with activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in both vessel types. The authors tested the hypothesis that this remodeling heterogeneity could be related to distinct vasoreactivity patterns in small and larger arteries, with a vessel-specific function of ERK1/2 signaling. Using intravital microscopy in rats we have demonstrated that acute NOS inhibition (l-NA injection, 100 mg/kg) produced vasoconstriction of small mesenteric arteries. Consequently, the calculated in vivo wall stress was not significantly modified, despite the local rise in pressure. This could explain the lack of vascular protein synthesis elevation in vivo, an early index of hypertrophy. Inhibition of ERK1/2 activation with PD98059 blunted mesenteric artery contractions. Femoral arteries did not contract and were thus submitted to an enhanced wall stress and underwent hypertrophic remodeling in chronic conditions. In conclusion, the heterogeneous vascular remodeling in the l-NAME model is associated with a heterogeneous vasoconstriction response to acute NOS inhibition. Indeed, in contrast to larger arteries, l-NA-induced vasoconstriction in small arteries normalized wall stress and prevented early signs of hypertrophy. The results also suggest that ERK1/2 is a signaling element in NOS inhibition-induced vasoconstriction of small arteries in vivo.
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PMID:ERK1/2-mediated vasoconstriction normalizes wall stress in small mesenteric arteries during NOS inhibition in vivo. 1296 Jun 78

Insulin resistance and compensatory hyperinsulinemia are recognized not only in type 2 diabetes mellitus(DM) but also in essential hypertension(EHT), hyperlipidemia and obesity; these are known as the components of metabolic syndrome and accumulation of these components increase risk of cardiovascular diseases(CVD). When coronary angiographic findings were evaluated in patients with coronary artery disease(CAD), the severity was higher in CAD with DM than that without DM. Even in CAD without DM, the severity of coronary angiographic findings was higher in CAD with insulin resistance than that without insulin resistance. When residents of rural communities in Japan were followed 8 years, the incidence of CVD was 3.5 times higher in subjects with insulin resistance than those without insulin resistance. One of the intracellular signal transduction of insulin receptor; MAP kinase may be concerned atherosclerotic mechanisms of insulin resistance. These findings suggest that insulin resistance is a significant background of atherosclerosis, and insulin resistance is one of the major facilitation factors of genesis and progression of CVD.
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PMID:[Significance of insulin resistance to atherosclerotic complications in essential hypertension]. 1473 36

The WNK kinases are a small group of serine/threonine kinases with unique catalytic domains that lack the lysine residue used in other kinases to co-ordinate ATP (hence, With No K [WNK]). Their closest homologues are found within the mitogen-activated protein kinase (MAPK) pathway suggesting a role in signalling. Two WNK isoforms, WNK1 and WNK4, have been identified as the disease genes for a rare monogenic hypertension syndrome (Gordon's syndrome or pseudohypoaldosteronism type 2 [PHA2]) implicating them in salt homeostasis by the kidney. This is supported by recent data showing widespread expression of WNK1 and WNK4 in mammalian transporting epithelia. Within the kidney, WNKs probably regulate the surface expression of several proteins involved in ion transport, including the sodium-chloride cotransporter (NCCT) and the potassium channel renal outer medullary potassium channel (ROMK), based on co-expression studies in Xenopus oocytes. WNKs, especially WNK4, have been suggested as candidate genes for essential hypertension itself, but evidence for this is lacking. Some of the effects of the WNKs are independent of their kinase function, suggesting that they are dependent on specific protein-protein interactions. It seems likely that the WNKs are part of much larger protein scaffolds in cells and have effects in cells beyond ion transport. However, because of their effect on expression of the NCCT they are attractive drug targets for the development of novel antihypertensive agents. These agents could potentially offer the efficacy of a thiazide diuretic, but without the metabolic side effects usually seen with this class of antihypertensive therapy.
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PMID:WNK kinases and the control of blood pressure. 1586 21


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