Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contraction by Activating Specific Protein Kinase C Isoforms

Sirous, Zohreh N; Fleming, J. B.; Khalil, Raouf A.

doi:10.1161/01.hyp.37.2.497

Cited by 28 publications

(32 citation statements)

References 34 publications

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“…This is supported by reports that ET stimulates diacylglycerol production and increases PKC activity in vascular smooth muscle. 42,43 The possible role of PKC in the enhanced vascular reactivity in ET-infused rats is further supported by the present observation that the enhancement of the 45 Ca 2ϩ influx-active stress relation was abolished in tissues pretreated with 2 mechanistically distinct PKC inhibitors, ie, GF109203X and calphostin C. 37 The present study showed that infusion of ET in NS rats caused modest, but not significant, elevation of arterial pressure. ET infusion in HS rats was associated with slightly greater elevations of arterial pressure, but these elevations were still not significant.…”

Section: Discussionsupporting

confidence: 61%

Endothelin-Induced Increases in Ca ²⁺ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

et al. 2003

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Abstract-High-salt diet is often associated with increases in arterial pressure, and a role for endothelin (ET)-1 in salt-sensitive hypertension has been suggested; however, the vascular mechanisms involved are unclear. We investigated whether ET increases the sensitivity of the mechanisms of vascular contraction to changes in dietary salt intake. Active stress and 45 Ca 2ϩ influx were measured in endothelium-denuded aortic strips of male Sprague-Dawley rats not treated or chronically infused intravenously with ET (5 pmol/kg per minute) and fed either normal-sodium diet (NS, 1%) or high-sodium diet (HS, 8%) for 9 days. Phenylephrine (Phe) caused increases in active stress that were similar in NS and HS, but were greater in NS/ET (maximum, 10.5Ϯ0.7) than in NS (maximum, 7.4Ϯ0.9) rats, and further enhanced in HS/ET (maximum, 14.4Ϯ1.1) compared with HS rats (maximum, 8.0Ϯ0.8ϫ10 4 N/m 2 ). Phe was more potent in causing contraction in NS/ET than in NS rats and in HS/ET than in HS rats. In Ca 2ϩ -free (2 mmol/L EGTA) Krebs, stimulation of intracellular Ca 2ϩ release by Phe (10 Ϫ5 mol/L) or caffeine (25 mmol/L) caused a transient contraction that was not significantly different in all groups of rats. In contrast, membrane depolarization by high-KCl solution, which stimulates Ca 2ϩ entry from the extracellular space, caused greater contraction in ET-infused rats, particularly those on HS diet. Phe (10 Ϫ5 mol/L) caused an increase in 45 Ca 2ϩ influx that was greater in NS/ET (27.9Ϯ1.7) than in NS (20.1Ϯ1.8) rats and further enhanced in HS/ET (35.2Ϯ1.8) compared with HS rats (21.8Ϯ1.9 mol/kg/min). The Phe-induced 45 Ca 2ϩ influx-stress relation was not different between NS and HS rats, but was enhanced in ET-infused rats particularly those on HS. The enhancement of the 45 Ca 2ϩ influx-active stress relation in ET-infused rats was not observed in vascular strips treated with the protein kinase C inhibitor GF109203X or calphostin C (10 Ϫ6 mol/L). Thus, low-dose infusion of ET, particularly during HS, is associated with increased vascular reactivity that involves Ca 2ϩ entry from the extracellular space, but not Ca 2ϩ release from the intracellular stores. The ET-induced enhancement of the Ca Key Words: arterial pressure Ⅲ endothelium Ⅲ vascular smooth muscle Ⅲ calcium Ⅲ contraction H igh-salt diet (HS) has been implicated in the pathogenesis of hypertension, particularly in salt-sensitive individuals, 1-4 and salt moderation is often recommended to protect against excessive increases in blood pressure. 1,2,5,6 Studies in salt-sensitive experimental animals such as the Dahl salt-sensitive rat have shown that HS is associated with significant increases in blood pressure. 7,8 Also, in saltsensitive rats, HS is associated with exaggerated vascular reactivity to vasoconstrictor stimuli, which may contribute, at least in part, to the increases in blood pressure. 9 -12 Although the mechanisms of salt-sensitive hypertension have not been clearly identified, several studies point to a possible role of endothelin (ET). 7,[13][14...

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Section: Discussionsupporting

confidence: 61%

Endothelin-Induced Increases in Ca ²⁺ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

et al. 2003

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“…Our laboratory, using the naturally-occurring C 16:0 and C 18:1 C1P, showed the lipid is a cofactor in the activation of cPLA 2 ␣ and synthesis of eicosanoids ( 7,8 ). Because eicosanoids pathways have roles in calcium homeostasis ( 13,14 ), cell survival ( 15 ), apoptosis ( 16 ), and cell growth ( 16 ), the question remains whether these biologies reported for C1P can be attributed simply to cPLA 2 ␣ activation. In addition, a recent paper by Tauzin et al ( 17 ) demonstrated that using dodecane to deliver phospholipids induced eicosanoid synthesis and loss of cell viability in a nonspecifi c manner, casting doubts on the validity of this well-established method of lipid delivery.…”

Section: Dispersion Of C1p In Etoh/dodecanementioning

confidence: 99%

Chain length specificity for activation of cPLA2α by C1P: use of the dodecane delivery system to determine lipid-specific effects

Wijesinghe

Subramanian

Lamour

et al. 2009

Journal of Lipid Research

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The fi rst report of a biological effect for ceramide-1-phosphate (C1P) was by , which demonstrated that short chain (not naturally found in cells) C1P induced DNA synthesis in Rat-1 fi broblasts. Later, treatment of T17 fi broblasts with long chain, natural C1P was also demonstrated to induce a potent increase in DNA synthesis ( 2 ) and the levels of proliferating nuclear antigen. Following this line of research, a recent report demonstrated that C1P prevented programmed cell death in bone marrow-derived macrophages after withdrawal of macrophage colony-stimulating factor ( 3 ). Treatment of these cells with C1P effectively blocked the activation of caspases and prevented DNA fragmentation upon serum removal.Abstract Previously, our laboratory demonstrated that ceramide-1-phosphate (C1P) specifi cally activated group IVA cytosolic phospholipase A 2 (cPLA 2 ␣ ) in vitro. In this study, we investigated the chain length specifi city of this interaction. C1P with an acyl-chain of ≥ 6 carbons effi ciently activated cPLA 2 ␣ in vitro, whereas C 2 -C1P, was unable to do so. Delivery of C1P to cells via the newly characterized ethanol/dodecane system demonstrated a lipid-specifi c activation of cPLA 2 ␣ , AA release, and PGE 2 synthesis (EC 50 = 400 nM) when compared to structurally similar lipids. C1P delivered as vesicles in water also induced a lipid-specifi c increase in AA release. Mass spectrometric analysis demonstrated that C1P delivered via ethanol/dodecane induced a 3-fold increase in endogenous C1P with little metabolism to ceramide. C1P was also more effi ciently delivered (>3-fold) to internal membranes by ethanol/dodecane as compared to vesiculated C1P. Using this now established delivery method for lipids, C 2 -C1P was shown to be ineffective in the induction of AA release as compared with C 6 -C1P, C 16 -C1P, and C 18:1 C1P. Here, we demonstrate that C1P requires ≥ 6 carbon acyl-chain to activate cPLA 2 ␣ . Thus, published reports on the biological activity of C 2 -C1P are not via eicosanoid synthesis. Furthermore, this study demonstrates that the alcohol/dodecane system can be used to effi ciently de-

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“…ET also activates plasma membrane Ca 2+ channels and stimulates Ca 2+ influx from the extracellular space [55,56]. The ET-induced increase in diacylglycerol stimulates PKC activity [57][58][59]. ET A receptor stimulation could also activate phospholipase D with generation of diacylglycerol, phospholipase A2 with release of arachidonic acid, the Na + /H + exchanger, Src-family tyrosine kinases, mitogen-activated protein kinase (MAPK), c-Jun-NH2-terminal kinase (JNK), p38 MAPK, and phosphatidylinositol 3-kinase [9,[60][61][62].…”

Section: Et Receptor-mediated Signaling Pathwaysmentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

104

105

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contraction by Activating Specific Protein Kinase C Isoforms

Cited by 28 publications

References 34 publications

Endothelin-Induced Increases in Ca ²⁺ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

Endothelin-Induced Increases in Ca ²⁺ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

Chain length specificity for activation of cPLA2α by C1P: use of the dodecane delivery system to determine lipid-specific effects

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

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Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contraction by Activating Specific Protein Kinase C Isoforms

Cited by 28 publications

References 34 publications

Endothelin-Induced Increases in Ca 2+ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

Endothelin-Induced Increases in Ca 2+ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

Chain length specificity for activation of cPLA2α by C1P: use of the dodecane delivery system to determine lipid-specific effects

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

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Endothelin-Induced Increases in Ca ²⁺ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

Endothelin-Induced Increases in Ca ²⁺ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet