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)

Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds on which the G protein-coupled receptor (GPCR)-induced signaling complex might assemble. We have recently reported that Ca2+-sensitive tyrosine kinase, Pyk2, and epidermal growth factor receptor (EGFR) act as independently regulated scaffolds in cardiomyocytes. In this report, we investigated the activation and regulation of p130Cas, Crk, Pyk2, and c-Src by a well-known hypertrophic agonist, endothelin-1 (ET), and determined their contributions to the activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in cardiomyocytes. Like Pyk2, ET-induced tyrosine phosphorylation of p130Cas was significantly inhibited by either chelating intracellular Ca2+ ([Ca2+]i) or a protein kinase C inhibitor, calphostin C. This activation of p130Cas was also abrogated by the tetrapeptide RGDS, which disrupts integrin heterodimerization; cytochalasin D, which depolymerizes the actin cytoskeleton; or a selective Src family kinase inhibitor, PP2, but not by an EGFR inhibitor, AG1478. We also observed ET-induced temporal associations of Pyk2 with active c-Src, followed by p130Cas with Pyk2, c-Src, and Crk. Overexpression of a dominant-negative mutant of p130Cas (CasDeltaSD), Crk (CrkSH2m), Pyk2 (PKM), or C-terminal Src kinase (Csk), but not of a deletion mutant of EGFR (533delEGFR), attenuated ET-induced JNK activation. Similarly, an ET-induced increase in c-jun promoter luciferase activity was inhibited by overexpression of CasDeltaSD, CrkSH2m, PKM, or Csk. In contrast, ET-induced ERK activation and c-fos gene expression were predominantly regulated by EGFR. Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes.
Hypertension 2003 Jun
PMID:Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation. 1271 47

Angiotensin II (AngII) regulates such physiological responses as salt and water balance, blood pressure, and vascular tone, and thus plays a critical role in the pathogenesis of diabetes, hypertension, myocardial infarction, congestive heart failure, and stroke. These effects are mediated through at least three receptors: AT1R, AT2R, and AT4R, which are expressed under different developmental, tissue-specific, and disease-specific conditions and which couple to distinct effector pathways. Signaling through the AT1R, a classical G protein-coupled receptor, has been extensively studied and is well understood. Less is known about signaling through the AT2R, which often antagonizes the effects of signaling through the AT1R, but intriguing data are beginning to emerge concerning the signaling strategies and pathways that the AT2R employs.
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PMID:Angiotensin type 2 receptor (AT2R): a challenging twin. 1273 84

G protein-coupled receptor kinases (GRKs) are key modulators of G protein-coupled receptor signalling. Increasing evidence points to the occurrence of complex mechanisms able to modulate the subcellular localization, activity and expression levels of GRKs, revealing new functional interactions of these kinases with different cellular proteins and transduction cascades. GRK activity and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins, caveolin and calcium-sensing proteins. In addition, GRK phosphorylation by several other kinases has recently been shown to modulate its functionality, thus putting forward new feedback mechanisms connecting different signalling pathways to G protein-coupled receptors (GPCR) regulation. On the other hand, the mechanisms governing GRK expression at both transcriptional and protein stability levels are just beginning to be unveiled. Namely, GRK2 has been shown to be rapidly degraded by the proteasome pathway in a process dependent on beta-arrestin and c-Src function, and also to be proteolyzed by m-calpain. A better knowledge of GRK regulatory mechanisms would contribute to greater understanding of GRK physiological function and also its reported alterations in different pathological situations, such as congestive heart failure, hypertension or inflammation.
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PMID:Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. 1449 40

Heart failure represents the endpoint to many triggering cardiovascular pathologies. However, there are molecular and biochemical features that remain common to the failing heart, despite the varying etiologies. Principal among these is heightened activation of the sympathetic nervous system and associated enhancement of adrenergic signaling pathways via the catecholamines, norepinephrine and epinephrine. During heart failure, several hallmark alterations in the adrenergic system contribute to loss of cardiac function. To specifically study these changes in a physiologically relevant setting, we and others have utilized advances in genetically engineered mouse technology. This chapter will discuss the many transgenic and knockout mouse models that have been developed to study the adrenergic system in the normal and failing heart. These models include genetically manipulated alterations of adrenergic receptors, linked heterotrimeric G proteins, and the regulatory G protein-coupled receptor kinases (GRKs). Among the more-interesting information gained from these models is the finding that inhibition of a particular GRK - GRK2 or beta adrenergic receptor kinase 1 (betaARK1) - is a potential novel therapeutic strategy to improve function in the setting of heart failure. Furthermore, we will discuss recent transgenic research that proposes an important role for hypertension in the development of heart failure. Overall, genetically engineered mouse models pertaining to this critical myocardial signaling system have provided novel insight into heart function under normal conditions and during states of dysfunction and failure.
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PMID:The adrenergic pathway and heart failure. 1474 95

The pronounced pharmacodynamic effects of human urotensin-II (U-II), a 'somatostatin-like' cyclic undecapeptide, are mediated via the G protein-coupled receptor UT (formerly known as GPR14). Emerging clinical studies implicate U-II in the etiology of several cardiorenal and metabolic disease states in humans. Although the specific pathogenic role(s) of U-II remain to be clearly defined, existing data warrant further clinical investigation. The therapeutic development of specific U-II/UT inhibitors will assist in establishing a causative role for U-II in the progression and/or maintenance of hypertension, heart failure, renal tubular disease and diabetes.
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PMID:Urotensin-II as a novel therapeutic target in the clinical management of cardiorenal disease. 1508 93

Agonist stimulation of certain G protein-coupled receptors (GPCRs) causes shedding of heparin-binding epidermal growth factor (HB-EGF) through activation of matrix metalloproteinases (MMPs), with subsequent transactivation of the EGF receptor. MMPs are widely expressed, and their dysregulated expression is crucial in cancer, inflammation, and cardiovascular remodeling. Recent studies in hypertensive animals have shown enhanced expression and activation of MMPs and EGF receptors, and their inhibition attenuates cardiac hypertrophy, vasoconstriction and hypertension induced by GPCR agonists such as angiotensin II, endothelin-1 and phenylepherine. These findings suggest that selective inhibition of MMPs might have therapeutic potential in hypertension and other cardiovascular diseases.
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PMID:Matrix metalloproteinase-dependent EGF receptor activation in hypertension and left ventricular hypertrophy. 1535 74

Phosphatidylinositol 3-kinase (PI3K) can activate endothelial nitric oxide synthase (eNOS), leading to production of the vasodilator NO. In contrast, vascular smooth muscle (VSM) PI3K may partially mediate vascular contraction, particularly during hypertension. We tested whether endothelial and VSM PI3K may have opposing functional roles in regulating vascular contraction. Secondly, we tested whether the procontractile protein rho-kinase can suppress endothelial PI3K/eNOS activity in intact arteries, thus contributing to vasoconstriction by G protein-coupled receptor (GPCR) agonists. We studied contractile responses to the GPCR agonist phenylephrine, and the receptor-independent vasoconstrictor KCl, in aortic rings from Sprague-Dawley rats. In endothelium-intact rings, the PI3K inhibitor wortmannin (0.1 microM) markedly augmented responses to phenylephrine (P < 0.05) by approximately 50% but not to KCl. However, in endothelium-denuded or N(G)-nitro-L-arginine methyl ester (L-NAME) (100 microM)-treated rings, wortmannin reduced responses to phenylephrine and KCl (P < 0.05). Furthermore, the rhokinase inhibitor Y-27632 (R-[+]-trans-N-[4-pyridyl]-4-[1-aminoethyl]-cycloheaxanecarboxamide; 1 microM) abolished responses to phenylephrine, and this effect was partially reversed by wortmannin or L-NAME. The ability of wortmannin to oppose the effect of rho-kinase inhibition on contractions to phenylephrine was L-NAME-sensitive. In aortas from angiotensin II-induced hypertensive rats, relaxation to acetylcholine (10 microM) was impaired (P < 0.05), and vasoconstriction by phenylephrine was markedly enhanced and not further augmented by wortmannin. These data suggest that endothelial PI3K-induced NO production can modulate GPCR agonist-induced vascular contraction and that this effect is impaired in hypertension in association with endothelial dysfunction. In addition, endothelial rho-kinase may act to suppress PI3K activity and, hence, attenuate NO-mediated relaxation and augment GPCR-dependent contraction.
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PMID:Opposing roles of endothelial and smooth muscle phosphatidylinositol 3-kinase in vasoconstriction: effects of rho-kinase and hypertension. 1574 31

Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein-coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)gamma are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kgamma was found to play a role in angiotensin II-evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kgamma was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kgamma was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca(2+) channel-mediated extracellular Ca(2+) entry. These data indicate that PI3Kgamma is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kgamma function might be exploited to improve therapeutic intervention on hypertension.
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PMID:Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. 1582 82

We have recently reported that lipid structure regulates the interaction with membranes, recruitment to membranes, and distribution to membrane domains of heterotrimeric Galphabetagamma proteins, Galpha subunits, and Gbetagamma dimers (J Biol Chem 279:36540-36545, 2004). Here, we demonstrate that modulation of the membrane structure not only determines G protein localization but also regulates the function of G proteins and related signaling proteins. In this context, the antitumor drug daunorubicin (daunomycin) and oleic acid changed the membrane structure and inhibited G protein activity in biological membranes. They also induced marked changes in the activity of the alpha(2A/D)-adrenergic receptor and adenylyl cyclase. In contrast, elaidic and stearic acid did not change the activity of the above-mentioned proteins. These fatty acids are chemical but not structural analogs of oleic acid, supporting the structural basis of the modulation of membrane lipid organization and subsequent regulation of G protein-coupled receptor signaling. In addition, oleic acid (and also daunorubicin) did not alter G protein activity in a membrane-free system, further demonstrating the involvement of membrane structure in this signal modulation. The present work also unravels in part the molecular bases involved in the antihypertensive (Hypertension 43:249-254, 2004) and anticancer (Mol Pharmacol 67:531-540, 2005) activities of synthetic oleic acid derivatives (e.g., 2-hydroxyoleic acid) as well as the molecular bases of the effects of diet fats on human health.
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PMID:Influence of the membrane lipid structure on signal processing via G protein-coupled receptors. 1583 42

The G protein-coupled receptor kinases (GRKs) participate with arrestins in the regulation and signal propagation of multiple G protein-coupled receptors (GPCR) of key physiological and pharmacological relevance in the cardiovascular system. The complex mechanisms of regulation of GRK expression, degradation and function are being unveiled gradually. The levels of these kinases are known to change in pathological situations such as heart failure, hypertrophy and hypertension, and in animal models of these diseases. A better understanding of the mechanisms underlying these changes and of how these alterations participate in the triggering or progression of cardiovascular disease may contribute to the design of novel diagnostic and therapeutic strategies.
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PMID:Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease. 1628 30


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