Elevated Endothelial Nitric Oxide Bioactivity and Resistance to Angiotensin-Dependent Hypertension in 12/15-Lipoxygenase Knockout Mice

Anning, Peter B.; Coles, Barry A.; Bermúdez-Fajardo, Alexandra; Martin, Patricia; Levison, Bruce S.; Hazen, Stanley L.; Funk, Colin D.; Kühn, Hartmut; O'Donnell, Valerie Bridget

doi:10.1016/s0002-9440(10)62287-0

Cited by 49 publications

(46 citation statements)

References 42 publications

(39 reference statements)

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“…To examine for differences in bioactivity of these mediators in IL-6 deficiency, responses were re-examined in the presence of either L-NAME or indomethacin to inhibit generation of NO or PGI, respectively. As expected from our previous studies with WT aortae, 22 inclusion of L-NAME potentiated constriction and inhibited relaxation because of inhibition of eNOS, whereas indomethacin had a small inhibitory effect on constriction ( Figure 5). Identical effects were found in rings from IL-6 Ϫ/Ϫ mice, indicating that a similar balance of NO and PGI is required to sustain tone ( Figure 5).…”

Section: In Vitro Studies On Vascular Reactivity Of Wt and Il-6 ϫ/ϫ Asupporting

confidence: 88%

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Coles

Fielding

Rose-John

et al. 2007

The American Journal of Pathology

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119

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Interleukin (IL)-6 acts via a receptor complex consisting of the cognate IL-6 receptor (IL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130).Here, we investigated the role of these IL-6R components in hypertension and vascular hypertrophy in mice. Angiotensin (Ang) II (1.1 mg/kg/day) caused hypertension and cardiac/aortic hypertrophy in wildtype, but not IL-6 ؊/؊ , mice throughout 7 days. A recombinant dimeric soluble gp130 (sgp130Fc; 50 to 100 g, i.p.) blocked Ang II hypertension but not hypertrophy in wild-type mice. Cognate IL-6R was detected in aortic smooth muscle, but its levels and those of plasma sIL-6R were ϳ50% decreased in IL-6 ؊/؊ mice. Ang II infusion activated signal transducer and activator of transcription-3 in heart of WT and decreased Ang II receptor 1 (ATR1) expression in aorta. Both responses were unaffected by sgp130Fc and absent in IL-6 ؊/؊ mice. In summary, we show that IL-6 trans-signaling is required for Ang II-dependent hypertension, but that hypertrophy, down-regulation of AT1R, and cardiac signal transducer and activator of transcription-3 activation are mediated via cognate IL-6R. These data show that IL-6 responses in a single disease context are governed by both modes of IL-6 signaling, with each pathway eliciting different outcomes. Inhibition of IL-6 signaling is suggested as a potential therapy for hypertension and cardiac hypertrophy. There is emerging evidence for a role of interleukin (IL)-6 and its related cytokines in angiotensin (Ang) II-dependent vascular dysfunction. Plasma levels of IL-6 are strongly associated with hypertension in humans and can be decreased by administration of Ang II receptor antagonists.

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Section: In Vitro Studies On Vascular Reactivity Of Wt and Il-6 ϫ/ϫ Asupporting

confidence: 88%

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Coles

Fielding

Rose-John

et al. 2007

The American Journal of Pathology

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119

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“…increased 'vascular reactivity') (Anning et al 2005;Touyz et al 2005;Hercule et al 2007;Ding et al 2007;Kirabo et al 2011;Kharade et al 2013). As SNA was not measured directly in our experiments, it was important to determine whether FA might have increased reactivity to sympathetic neurotransmitters.…”

Section: Arterial Reactivitymentioning

confidence: 96%

“…Acute blockade of autonomic ganglionic transmission causes a larger fall in mean arterial BP, a 'depressor' response, in Ang II-infused animals compared to controls (Kuroki et al 2012). Thus, increased arterial pressure after Ang II treatment involves increased SNA, or increased efficacy of SNA, as might be the result of increased 'vascular reactivity' (Anning et al 2005;Touyz et al 2005;Ding et al 2007;Hercule et al 2007;Kirabo et al 2011;Kharade et al 2013). Because increased SNA may be region specific (Yoshimoto et al 2010), it was unknown whether Ang II treatment increased SNA or SNA efficacy in FA.…”

Section: Local Vascular Ang II Receptor Activation Mediates a Small Cmentioning

confidence: 99%

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Intravital Förster resonance energy transfer imaging reveals elevated [Ca²⁺]_i and enhanced sympathetic tone in femoral arteries of angiotensin II‐infused hypertensive biosensor mice

Wang¹,

Chen

Wier³

et al. 2013

The Journal of Physiology

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Key points• It is desirable to study altered artery function in hypertension in living animals, where factors influencing artery function are intact.• We infused 'biosensor' mice chronically with angiotensin II to produce hypertension, and used intravital Förster resonance energy transfer microscopy to measure, simultaneously, [Ca 2+ ] i and artery diameter in vivo.• Femoral arteries in hypertensive mice had increased basal (resting) [Ca 2+ ] i and were more constricted than femoral arteries in saline-infused mice. These differences were abolished by blocking (1) all peripheral sympathetic nerve activity (SNA), or (2) vascular α 1 -adrenoceptors, but not by blocking vascular angiotensin II or arginine vasopressin receptors.• Neither contractility nor structural changes were found in femoral arteries of angiotensin II-infused mice.• The results support previous suggestions that angiotensin II infusion raises blood pressure by acting on the CNS to increase SNA, which increases smooth muscle [Ca 2+ ] i . Infused angiotensin II does not act directly on arterial angiotensin II receptors.Abstract Artery narrowing in hypertension can only result from structural remodelling of the artery, or increased smooth muscle contraction. The latter may occur with, or without, increases in [Ca 2+ ] i . Here, we sought to measure, in living hypertensive mice, possible changes in artery dimensions and/or [Ca 2+ ] i , and to determine some of the mechanisms involved. Ca 2+ /calmodulin biosensor (Förster resonance energy transfer-based) mice were made hypertensive by S.C. infusion of angiotensin II (Ang II, 400 ng kg −1 min −1 , 2-3 weeks). Intravital fluorescence microscopy was used to determine [Ca 2+ ] i and outer diameter of surgically exposed, intact femoral artery (FA) of anaesthetized mice. Active contractile FA 'tone' was calculated from the basal-state diameter and the passive (i.e. Ca 2+ -free) diameter (PD). Compared to saline control, FAs of Ang II-infused mice had (1) ∼21% higher active tone and (2) ∼78 nM higher smooth muscle [Ca 2+ ] i , but (3)

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“…12/15-Lipooxygenase inhibition or gene deletion blunts the pressor response to ANG II and blocks ANG II-induced hypertrophy and ECM accumulation in rat mesangial cells (85). Also, 12/15-lipooxygenase deficiency is associated with increased eNOS expression/activity, suggesting a relation between the two pathways in the control of vascular function (5). Urinary excretion of 12-HETE is increased in essential HTN.…”

Section: Renal Endothelial Cell Dysfunction In Htnmentioning

confidence: 99%

Cellular mediators of renal vascular dysfunction in hypertension

Ponnuchamy¹,

Khalil²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Ponnuchamy B, Khalil RA. Cellular mediators of renal vascular dysfunction in hypertension. Am J Physiol Regul Integr Comp Physiol 296: R1001-R1018, 2009. First published February 18, 2009 doi:10.1152/ajpregu.90960.2008.-The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/ defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A 2. Also, an increase in the amount/activity of intracellular Ca 2ϩ concentration, protein kinase C, Rho kinase, and mitogenactivated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN. blood pressure; dietary salt; oxidative stress; cytokines; kidney; endothelium; vascular smooth muscle; extracellular matrix; matrix metalloproteinases THE ROLE OF THE KIDNEY IN the regulation of sodium and water balance and blood pressure (BP) is well recognized (53,55,128). A decrease in plasma volume and renal blood flow (RBF) stimulates renin release from the juxtaglomerular cells (JGCs) and activates the renin-angiotensin system (RAS). Renin transforms angiotensinogen to angiotensin I (ANG I), and angiotensin-converting enzyme (ACE) transforms ANG I to ANG II. ANG II stimulates the adrenal cortex to release aldosterone (Aldo), which acts on the rena...

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Elevated Endothelial Nitric Oxide Bioactivity and Resistance to Angiotensin-Dependent Hypertension in 12/15-Lipoxygenase Knockout Mice

Cited by 49 publications

References 42 publications

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Intravital Förster resonance energy transfer imaging reveals elevated [Ca²⁺]_i and enhanced sympathetic tone in femoral arteries of angiotensin II‐infused hypertensive biosensor mice

Cellular mediators of renal vascular dysfunction in hypertension

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Elevated Endothelial Nitric Oxide Bioactivity and Resistance to Angiotensin-Dependent Hypertension in 12/15-Lipoxygenase Knockout Mice

Cited by 49 publications

References 42 publications

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

Intravital Förster resonance energy transfer imaging reveals elevated [Ca2+]i and enhanced sympathetic tone in femoral arteries of angiotensin II‐infused hypertensive biosensor mice

Cellular mediators of renal vascular dysfunction in hypertension

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Intravital Förster resonance energy transfer imaging reveals elevated [Ca²⁺]_i and enhanced sympathetic tone in femoral arteries of angiotensin II‐infused hypertensive biosensor mice