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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular wall is constantly subjected to a variety of mechanical forces in the form of stretch (tensile stress), due to blood pressure, and shear stress, due to blood flow. Alterations in either of these stresses are known to result in vascular remodeling, an adaptation characterized by modified morphology and function of the blood vessels, allowing the vessels to cope with physiological or pathological conditions. The processes involved in vascular remodeling include cellular hypertrophy and hyperplasia, as well as enhanced protein synthesis or extracellular matrix protein reorganization. In vitro studies using vascular cells have attempted to identify the mechanisms behind structural alterations. Possible pathways include ion channels, integrin interaction between cells and the extracellular matrix, activation of various tyrosine kinases (such as c-Src, focal adhesion kinase, and mitogen-activated protein kinases), and autocrine production and release of growth factors. These pathways lie upstream of de novo synthesis of immediate response genes and total protein synthesis, both of which are likely to be involved in the process of vascular remodeling.
Hypertension 1998 Aug
PMID:Signal transduction of mechanical stresses in the vascular wall. 971 64

Phenotypic modulation of smooth muscle cells is closely associated with vasculogenesis, enterogenesis and some diseases such as atherosclerosis, hypertension and leiomyogenic tumorigenicity. During phenotypic modulation, smooth muscle cells change their morphology, cell function and biochemical characteristics. Recent studies have focused on the regulation mechanism of smooth muscle cell-specific genes at the levels of transcription and/or alternative splicing in a phenotype-dependent manner. Typical examples of such genes include caldesmon, alpha-tropomyosin, myosin heavy chain, SM22, calponin and alpha 1 integrin. Cell adhesion molecules and growth factors/cytokines also play a critical role for controlling phenotype of smooth muscle cells via signal transduction pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinases.
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PMID:Molecular mechanism of phenotypic modulation of smooth muscle cells. 972 87

Hypertension increases mechanical force on the arterial wall by as much as 30%, resulting in marked alterations in signal transductions and gene expression in vascular smooth muscle cells (VSMCs) that contribute to matrix protein synthesis, cell proliferation, and differentiation. How the mechanical stimuli are converted into a biological signal in cells has yet to be studied. We investigated the role of both cyclic strain and shear stresses in initiating the cellular signaling on cultured VSMCs and found that mechanical forces evoked activation of mitogen-activated protein kinases, followed by enhanced DNA binding activity of transcription factor AP-1. Physical forces rapidly induced phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti-phosphotyrosine, -PDGFR alpha, and -GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFR alpha bands of the same blot in stretch-stressed VSMCs, supporting the mechanical stress-induced activation of PDGFR alpha. Conditioned medium from stretch-stressed VSMCs did not result in PDGFR alpha phosphorylation, and antibodies binding to all forms of PDGFs did not block stress-induced PDGFR alpha activation. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signaling pathways normally used by growth factors.
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PMID:Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress. 973 16

Two subgroups of mitogen-activated protein kinases, c-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), are thought to be involved in cultured cardiac myocyte hypertrophy and gene expression. To examine the in vivo activation of these kinases, we measured cardiac JNK and ERK activities in conscious rats subjected to acute or chronic angiotensin II (Ang II) infusion, by using in-gel kinase methods. About 50 mm Hg rise in blood pressure by Ang II (1000 ng . kg-1 . min-1) infusion caused larger activation of left ventricular JNK than ERK, via the AT1 receptor. In spite of short duration (about 30 minutes) of maximal blood pressure elevation by Ang II, JNK sustained the peak value (more than 5-fold increase) from 15 minutes up to at least 3 hours. Similar activation of JNK was seen in the right ventricle. Thus, cardiac JNK activation by Ang II seems to be in part mediated by its direct action via the AT1 receptor. The dose-response relationships for Ang II-induced rises in blood pressure and cardiac JNK and ERK activation indicated that cardiac JNK or ERK was not activated by a mild increase in blood pressure and that cardiac JNK was activated by Ang II-mediated hypertension in a more sensitive manner than ERK. Cardiac hypertrophy, induced by chronic Ang II infusion, was preceded by JNK activation without ERK activation. Furthermore, gel mobility shift analysis showed that cardiac JNK activation was followed by increased activator protein-1 DNA binding activity due to c-Fos and c-Jun. These results provided the first evidence for the preferential activation of cardiac JNK in Ang II-induced hypertension and suggested that JNK might play some role in Ang II-induced cardiac hypertrophic response in vivo. However, further study is needed to elucidate the role of JNK in cardiac hypertrophy in vivo.
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PMID:Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated kinase in angiotensin II-mediated hypertension. 975 46

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.
Hypertension 1999 Jan
PMID:Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. 993 Nov 33

The present study examined the hypothesis that activation of protein kinase C (PKC), components of the mitogen-activated protein (MAP) kinase pathway, or both contributes to the inhibitory effects of 20-hydroxyeicosatetraenoic acid (20-HETE) on K+-channel activity and its vasoconstrictor response in renal arterioles. 20-HETE (0.1 to 50 micromol/L) dose-dependently produced a 30% increase in PKC activity and a fivefold rise in the expression of active extracellular signal-regulated kinase 1 (ERK1) and ERK2 proteins in renal microvessels. 20-HETE (0.01 to 1 micromol/L) reduced the diameter of isolated perfused renal interlobular arterioles by 33+/-2%. Blockade of PKC activity with an N-myristoylated PKC pseudosubstrate inhibitor (Myr-PKCi, 100 micromol/L) or calphostin C (0.5 micromol/L) had no significant effect on the vasoconstrictor response to 20-HETE. In contrast, the tyrosine kinase inhibitors genistein (30 micromol/L) and tyrphostin 25 (10 micromol/L) reduced the response to 20-HETE by 76.5+/-2.1% and 67.5+/-1.8%, respectively. A specific inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK), PD98059, had no effect on the vasoconstrictor response to 20-HETE. In cell-attached patches on renal vascular smooth muscle cells, 20-HETE reduced the open state probability of a large-conductance K+ channel (from 0.0026+/-0.0004 to 0.0006+/-0.0001). The Myr-PKCi (100 micromol/L) did not alter the inhibitory effects of 20-HETE on this channel. In contrast, the tyrosine kinase inhibitor genistein (30 micromol/L) blocked the inhibitory effects of 20-HETE on the large-conductance K+ channel. These data suggest that 20-HETE activates the MAP kinase system in renal arterioles and that the activation of a tyrosine kinase, which is proximal to MEK in this cascade, contributes to the inhibitory effects of 20-HETE on K+-channel activity and its vasoconstrictor effects in the renal arterioles.
Hypertension 1999 Jan
PMID:Role of tyrosine kinase and PKC in the vasoconstrictor response to 20-HETE in renal arterioles. 993 Nov 39

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.
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PMID:Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress. 1007 20

Mechanical stretch induced by high blood pressure is an initial factor leading to cardiac hypertrophy. In an in vivo study, an angiotensin II (AngII) type 1 receptor antagonist TCV116 reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine did not. In an in vitro study using cultured cardiomyocytes, mechanical stretch activated second messengers such as mitogen-activated protein (MAP) kinase, followed by increased protein synthesis. Additionally, in the stretch-conditioned medium AngII and endothelin-1 concentrations were increased. Furthermore, the Na+/H+ exchanger activated by mechanical stretch modulated the hypertrophic responses of cardiomyocytes. The pathways leading to MAP kinase activation differed between cell types. In cardiac fibroblasts AngII activated MAP kinase via G beta gamma subunit of Gi, Src, Shc, Grb2, and Ras, whereas Gq and protein kinase C were critical in cardiomyocytes.
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PMID:The molecular mechanism of cardiac hypertrophy and failure. 1041 19

While vascular smooth muscle cell proliferation is important in hypertension, relatively little is known about the contribution of catecholamines. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit angiotensin II-, basic fibroblast growth factor (FGF)-induced growth of vascular smooth muscle cells. We hypothesize that these agents might also inhibit the effect of the stimulation of alpha1-adrenoreceptors on the proliferation of vascular smooth muscle cells. Troglitazone (1-20 microM), a member of the thiazolidinediones, significantly inhibited the stimulation of alpha1-adrenoreceptor-induced DNA synthesis, c-fos induction and mitogen-activated protein (MAP)-kinase activation. This effect was associated with inhibition by troglitazone of the transactivation of the serum response element (SRE), which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via blockade of the upstream of MAP kinase activation in vascular smooth muscle cells. At this dose, troglitazone inhibited the ternary complex factor (TCF)-dependent activation, which is regulated by MAP kinase activation, but did not inhibit the TCF-independent SRE activation. Besides, the degree of the inhibitory effect of troglitazone on MAP kinase activation, DNA synthesis, c-fos expression differs. This may show that troglitazone work on multiple sites. These results suggest that troglitazone is a potent inhibitor of vascular smooth muscle cells proliferation through the downregulation of c-fos expression and may be a useful agent for prevention of atherosclerosis which is a result of hypertension.
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PMID:Troglitazone inhibits alpha1-adrenoceptor-induced DNA synthesis in vascular smooth muscle cells. 1042 49


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