Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKCδ

Allahdadi, Kyan James; Duling, Laura; Walker, Benjimen R.; Kanagy, Nancy L.

doi:10.1152/ajpheart.01264.2007

Cited by 39 publications

(40 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In agreement with previous findings using endotheliumdisrupted mesenteric arteries (Allahdadi et al, 2008b), this study demonstrates that augmented ET-1-mediated vasoconstriction is dependent on PKCd in endothelium-intact mesenteric arteries. This PKCd-dependent mechanism does not appear to be present in all vascular beds since isolated aortic segments from sham-and IH-exposed rats both show attenuated vasoconstriction in response to pan-PKC and cPKC inhibitors but PKCd inhibition has no effect (Allahdadi et al, 2008b).…”

Section: Discussionsupporting

confidence: 93%

“…This PKCd-dependent mechanism does not appear to be present in all vascular beds since isolated aortic segments from sham-and IH-exposed rats both show attenuated vasoconstriction in response to pan-PKC and cPKC inhibitors but PKCd inhibition has no effect (Allahdadi et al, 2008b). Furthermore, inhibition of PDK-1, a kinase activator of PKCd, with OSU-03012 attenuates ET-1-mediated vasoconstriction in arteries from IH-but not from sham-exposed rats.…”

Section: Discussionmentioning

confidence: 98%

“…Arteries from IH-exposed rats also have increased expression of the ET A R, and the increased vasoconstrictor sensitivity to ET-1 in IH rats can be attenuated by pharmacologically blocking ET A R (Allahdadi et al, 2005(Allahdadi et al, , 2008a. We subsequently reported that IH-augmented vasoconstriction is mediated by the d-isoform of protein kinase C (PKCd) in a calcium-independent manner and that ET-1 increases PKCd autophosphorylation levels (Allahdadi et al, 2008b). However, it is not clear what increases ET-1 activation of PKCd-dependent contraction in vascular smooth muscle from IH-exposed rats.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phosphoinositide-Dependent Kinase-1 and Protein Kinase CδContribute to Endothelin-1 Constriction and Elevated Blood Pressure in Intermittent Hypoxia

Webster

Osmond

Paredes

et al. 2012

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension. Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats. IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) d-dependent manner in mesenteric arteries. Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKCd activity, we hypothesized that PDK-1 contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH. Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O 2 /0% CO 2 and 5% O 2 /5% CO 2 ) conditions for 7 h/day for 14 or 21 days. The contribution of PKCd and PDK-1 to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors. Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats. Inhibition of PKCd or PDK-1 blunted ET-1 constriction in arteries from IH but not sham group rats. Western analysis revealed similar levels of total and phosphorylated PDK-1 in arteries from sham and IH group rats but decreased protein-protein interaction between PKCd and PDK-1 in arteries from IH-compared with sham-exposed rats. Blood pressure was increased in rats exposed to IH, and treatment with the PDK-1 inhibitor OSU-03012 [2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide] (33 mg/day) lowered blood pressure in IH but not sham group rats. Our results suggest that exposure to IH unmasks a role for PDK-1 in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions. These novel findings suggest that PDK-1 may be a uniquely effective antihypertensive therapy for OSA patients.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphoinositide-Dependent Kinase-1 and Protein Kinase CδContribute to Endothelin-1 Constriction and Elevated Blood Pressure in Intermittent Hypoxia

Webster

Osmond

Paredes

et al. 2012

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both are supported by our previous observations that these arteries have a modest increase in the protein levels of the ET A receptor and that postreceptor signal transduction is altered by E-IH exposure (4,5). Indeed, ET A receptors appear to activate PKC␦ in arteries from E-IH-exposed rats but not in sham arteries, further indicating that E-IH alters the signaling cascade of this receptor in vascular smooth muscle (3). Recent studies in diabetic rats also found that despite elevated levels of ET-1, vascular sensitivity to ET-1 was increased in small but not large arteries (53).…”

Section: ) Et B Receptor Mrna Expression Is Not Different In Tissuessupporting

confidence: 78%

Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

Allahdadi

Cherng²,

Pai³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Allahdadi KJ, Cherng TW, Pai H, Silva AQ, Walker BR, Nelin LD, Kanagy NL. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia. Am J Physiol Heart Circ Physiol 295: H434-H440, 2008. First published May 30, 2008 doi:10.1152/ajpheart.91477.2007.-We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ETA) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 Ϯ 2 to 137 Ϯ 4 mmHg; P Ͻ 0.005) but did not change in sham-exposed rats. The ETA receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol ⅐ kg Ϫ1 ⅐ day Ϫ1 sc for 14 days) prevented E-IHinduced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ETA receptor antagonist BQ-123 (10 M) but not by the ET type B (ET B) receptor antagonist BQ-788 (100 M). ETA receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ETB receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ETA receptors appears to elevate blood pressure in E-IHexposed rats. sleep apnea; BQ-123; BQ-788; mitochondrial ribonucleic acid OBSTRUCTIVE SLEEP APNEA is characterized by repeated upper airway obstruction during sleep and affects between 5% and 20% of the population (32). This syndrome of sleep-disordered breathing leads to episodic hypoxia and sleep deprivation. Recent epidemiological studies reveal that sleep apnea and other forms of sleep-disordered breathing increase the risk for hypertension and associated metabolic disorders (24). However, the mechanisms whereby sleep apnea and the associated eucapnic intermittent hypoxia (E-IH) cause systemic hypertension remain incompletely understood. Recent studies show that patients with sleep apnea have increased circulating levels of endothelin (ET)-1 (29, 42), a potent vasoconstrictor and mitogenic peptide implicated in the development of many forms of arterial hypertension (1). Furthermore, the synthesis of ET-1 is increased by hypoxia, shear stress, oxidative stress, and catecholamines, which are elevated in E-IH-exposed rats and sleep apnea (42, 47). We have previously described that both blood pressure and plasma ET-1 levels are incre...

show abstract

“…PKC activation not only mediates ET-1-induced vascular contraction (2,16,123) and regulates ET-1 receptors expression (112), but is intimately linked to ET-1-mediated regulation of hypertrophy, growth, proliferation, and survival in vascular smooth muscle cells (12). PKC activation (PKC-␦), via phosphorylation of STAT3, also mediates ET-1-induced decreases in arterial eNOS protein levels and NO generation (150) as well as ET-1-induced vascular formation of superoxide anion (103).…”

Section: Signaling Pathways Activated By Et-1 That Can Be Modified Bymentioning

confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Glycosylation with Olinked ␤-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET A and ETB receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed. endothelin receptor; vascular signaling; O-GlcNAc modification GLYCOSYLATION IS THE SITE-specific enzymatic addition of saccharides to proteins and lipids. There are many types of glycosylation, but great interest has been directed to O-GlcNAcylation, or glycosylation with O-linked ␤-N-acetylglucosamine or ␤-Olinked 2-acetamido-2-deoxy-D-glycopyranose (54,55,169). In this unusual form of protein glycosylation, a single sugar [␤-N-acetylglucosamine (O-GlcNAc)] is added to serine and threonine residues of nuclear or cytoplasmic proteins (54,55,169).Considering that almost every functional class of proteins is subject to O-GlcNAcylation (55, 177), this specific posttranslational modification has been implicated in several biological functions, including transcription or translation, stress responses, and energy metabolism. Proteins with an important role in vascular function are also targets for O-GlcNAcylation. Examples include endothelial nitric oxide (NO) synthase (eNOS), sarcoplasmic reticulum calcium (Ca 2ϩ )-ATPase (SERCA), phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and proteins involved in cytoskeleton regulation and microtubule assembly (22,55,177), indicating that this posttranslational modification may play an important role in vascular (...

show abstract

Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKCδ

Cited by 39 publications

References 43 publications

Phosphoinositide-Dependent Kinase-1 and Protein Kinase CδContribute to Endothelin-1 Constriction and Elevated Blood Pressure in Intermittent Hypoxia

Phosphoinositide-Dependent Kinase-1 and Protein Kinase CδContribute to Endothelin-1 Constriction and Elevated Blood Pressure in Intermittent Hypoxia

Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Contact Info

Product

Resources

About