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Hypertension. 2003;41:898-902
Published online before print March 10, 2003, doi: 10.1161/01.HYP.0000061762.58873.2F
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(Hypertension. 2003;41:898.)
© 2003 American Heart Association, Inc.


Scientific Contributions

PI3-Kinase–Induced Hyperreactivity in DOCA-Salt Hypertension Is Independent of GSK-3 Activity

Robert D. Loberg; Carrie A. Northcott; Stephanie W. Watts; Frank C. Brosius, III

From the Departments of Internal Medicine and Physiology, University of Michigan (R.D.L., F.C.B.), Ann Arbor, Mich; and Department of Pharmacology and Toxicology, Michigan State University (C.A.N., S.W.W.), East Lansing, Mich.

Correspondence to Frank C. Brosius, University of Michigan, 1560 MSRB2, 1150 W. Medical Center Dr, Ann Arbor, MI 48109-0676. E-mail fbrosius{at}umich.edu


*    Abstract
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*Abstract
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Phosphatidylinositol 3-kinase (PI3K) activity is increased in aortae from deoxycorticosterone (DOCA)-salt rats and enhanced PI3K activity contributes to the arterial hyperreactivity in these animals. Because PI3K activity is increased in DOCA-salt hypertension, we postulated that phosphorylation of Akt and glycogen synthase kinase 3 (GSK-3), serine threonine kinases that are downstream of PI3K, would be increased in DOCA-salt hypertension. In this study, we focused on GSK-3. Because GSK-3 activity is reduced by phosphorylation, we expected that its activity would be reduced in DOCA-salt hypertensive arteries and that reduced GSK-3 activity could contribute to enhanced adrenergic signaling and vascular smooth muscle hypertrophy that augment the heightened contractile response in DOCA-salt hypertension. Surprisingly, we observed a decrease in phosphorylation of GSK-3, indicating an increase in GSK-3 activity. To determine whether increased GSK-3 activity contributes to altered arterial reactivity in DOCA-salt animals, we measured isometric contraction to norepinephrine (NE) in the presence and absence of PI3K or GSK-3 inhibition. Addition of LY294002 (20 µmol/L), a PI3K inhibitor, resulted in a rightward shift in response to NE and normalized the NE-induced contractions in the DOCA hypertensive vessels. SB415286, a GSK-3 inhibitor, resulted in a slight rightward shift in response to NE in the DOCA-salt vessels. Thus, enhanced GSK-3 activity modestly augments the effects of PI3K but does not appear to contribute greatly to the altered arterial reactivity in DOCA-salt hypertension.


Key Words: muscle, smooth, vascular • glycogen synthase kinase 3 • deoxycorticosterone • hypertension, sodium-dependent


*    Introduction
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Arteries isolated from hypertensive animals consistently demonstrate potentiated contractions to a variety of agonists, and recent evidence has underlined the importance of phosphatidylinositol 3-kinase (PI3K) activity in this potentiation.1–5 For example, Northcott et al5 have demonstrated that PI3K activity is elevated in aortae from rats with DOCA-salt hypertension and that the increased activity contributes to enhanced arterial reactivity.

To investigate the mechanisms involved in the PI3K-mediated contractile response seen in arteries from DOCA-salt hypertensive animals, we have focused on the downstream serine-threonine kinase, glycogen synthase kinase 3 (GSK-3). GSK-3 is a ubiquitously expressed kinase that was first characterized as a major regulator of glycogen synthase activity.6 GSK-3 is a direct substrate of PKB/Akt7 and functions in several signaling pathways, including the PI3K pathway, to affect protein synthesis, carbohydrate metabolism, gene transcription, and apoptosis.8 Of the 2 known GSK-3 isoforms, the ß isoform is best characterized and seems to be predominant in adult tissues.9 In contrast to most serine-threonine kinases, activity of GSK-3 is reduced by phosphorylation and increased by dephosphorylation. Hence, PI3K and resultant Akt activation cause GSK-3 inactivation.

GSK-3 activity has been shown to be regulated by both {alpha} and ß adrenergic receptor activation.10,11 Activation of {alpha} adrenergic receptors induces phosphorylation of GSK-3ß, the major GSK-3 isoform, thus inhibiting its activity.11 In addition, phosphorylation and inhibition of GSK-3ß leads to cardiac hypertrophy, which can be prevented by overexpression of active GSK-3ß.12 Because PI3K activity is increased in DOCA-salt hypertension, we postulated that GSK-3ß activity would be reduced in this model and that persistent inhibition of GSK-3ß would in turn contribute to the augmented adrenergic signaling and/or to vascular smooth muscle hypertrophy that might augment the contractile response. However, in contrast to this hypothesis, we have observed a decrease in GSK-3 phosphorylation and an increase in GSK-3 activity. In addition, we have confirmed a decrease in Akt phosphorylation in arteries from DOCA-salt hypertensive animals. These results are unexpected because phosphorylation of both enzymes is usually increased when PI3K activity is enhanced. We have also tested the role of GSK-3 activity on the enhanced reactivity observed in arteries from DOCA-salt hypertensive animals and have found that it has only a minor effect on vascular reactivity in this model.


*    Methods
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*Methods
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Materials
Polyclonal antibodies for phosphoGSK-3{alpha}Ser9/21, total Akt, phosphoAktThr308, and phosphoPDK1Ser241 were obtained from Cell Signaling Technology. The antibody for total GSK-3{alpha} was from Upstate Biotechnology. Antibodies for total PKB kinase/PDK1-BD were from Transduction Laboratories. SB216763 and SB415286 were obtained from GlaxoSmithKline. All other compounds were from Sigma-Aldrich Corporation.

Animal Models
Male Sprague Dawley rats (250 to 300 g; Charles River Laboratories Inc, Portage, Mich) were uninephrectomized and impregnated with a subcutaneous silastic implant containing DOCA (200 mg/kg) under isoflurane anesthesia as described previously.13 Animals were maintained on water containing 1.0% NaCl and 0.2% KCl for 4 weeks. Sham animals were uninephrectomized but did not receive a DOCA implant and were maintained on normal drinking water. Systolic blood pressures were measured using standard tail-cuff procedures.

Arterial Reactivity
Endothelial cell-denuded or intact strips of thoracic aortae and carotid arteries were removed from pentobarbital (60 mg kg-1, IP) anesthetized rats and were mounted in isolated tissue baths for measurement of isometric force.13 Tissues were preincubated in the presence of SB415286 (1 µmol/L and 10 µmol/L) for 1 hour before measurements of contractility. Norepinephrine (NE, 1x10-9 to 3x10-5 mol/L) was added in a cumulative fashion after preincubation with inhibitors.

Immunoblotting
Aortae and carotid arteries were cleaned and pulverized in liquid nitrogen and solubilized in lysis buffer and prepared as previously reported.14 Whole cell lysates were separated by SDS-PAGE and immunoblotting was performed as previously reported.5,14

GSK-3 Activity Assay
Tissue homogenates from aortae and carotid arteries were prepared as described above using a homogenization buffer comprised of HEPES pH 7.5 (50 mmol/L), EGTA (1 mmol/L), EDTA (1 mmol/L), ß-glycerophosphate (10 mmol/L), sodium pyrophosphate (5 mmol/L), potassium chloride (100 mmol/L), Triton X-100 (0.5%), benzamidine (1 mmol/L), PMSF (0.1 mmol/L), aprotonin (10 µg/mL), vanadate (0.5 mmol/L), and dithiothreitol (1 mmol/L). In some samples, the GSK-3 inhibitor, SB415286, was added to the homogenization buffer before sample preparation for control experiments. Homogenates were sonicated for 10 seconds at 40% duty cycle (Sonicator Vibracell, Sonics and Materials Inc) and were centrifuged at 13 000 rpm for 20 minutes at 4°C. The supernatants were transferred to fresh microfuge tubes and protein concentrations were determined by bicinchoninic acid (BCA) protein assay (Pierce). Samples (10 µg) were added to 5 µL of 5x reaction buffer (HEPES [250 mmol/L], MgCl2 [50 mmol/L], and 2.5 mg/mL phosphoglycogen synthase peptide-2 substrate [Upstate Biotechnology]) and preincubated for 2 minutes at 30°C. The reaction was initiated by the addition of 250 µmol/L ATP and 2 µCi/10 µL 32P-{gamma}-ATP (Amersham) and incubated at 30°C for 15 minutes. Addition of 200 mmol/L EDTA+5 mmol/L ATP terminated the reaction and samples were transferred to Whatman P81 filter paper and washed 3 times in 100 mmol/L phosphoric acid followed by a final rinse in 95% ethanol. Filter paper was allowed to air dry and radioactivity was assessed by scintillation counting.

Data Analyses
Data are presented as mean±standard error of the mean. Contraction EC50 values were determined using GraphPad Prism® and reported as the mean of the negative logarithm (-log) of the EC50 value. Band density quantitation was performed using National Institutes of Health (NIH) Image (v.1.61). When comparing 2 groups, a Student t test was used. For multiple comparisons, an ANOVA followed by Student-Newman-Keuls or Bonferroni post hoc tests was performed. Probability values <=0.05 were considered statistically significant.


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Arteries from DOCA-salt hypertensive rats and normotensive controls (systolic blood pressure: DOCA 180.5±4.17; sham 115.63±2.39 mm Hg) were isolated and vascular reactivity was assessed. As previously reported,5 inhibition of PI3K with LY294002 attenuated the enhanced norepinephrine-induced reactivity seen in arteries from DOCA-salt rats, (-log EC50 values [mol/L]: DOCA -7.85±0.15 versus DOCALY294002 -6.80±0.14) (Figure 1), confirming the functional effect of enhanced PI3K activity in hypertensive vessels. Incubation with LY294002 more modestly reduced reactivity in normotensive aortae (-log EC50 values [mol/L]: sham -6.97±0.2 and shamLY294002 -6.48±0.14). Similar results were found in carotid arteries from both hypertensive and normotensive animals (-log EC50 values [mol/L]: DOCA -8.36±0.19 versus DOCALY294002 -7.33±0.07 and sham -8.26±0.32 versus shamLY294002 -7.42±0.06).



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Figure 1. Effect of PI3 kinase inhibitor LY294002 (20 µmol/L) on norepinephrine-induced contraction in aortae (A) and carotid arteries (B) from normotensive and DOCA-salt hypertensive rats. Data are reported as a percentage of the maximum norepinephrine-induced contraction (mean±SEM). *P<0.05.

To determine whether enhanced PI3K activity resulted in increased phosphorylation of the downstream kinase, GSK-3ß, we evaluated phosphoGSK-3 levels in arteries from DOCA-salt and normotensive rats. Surprisingly, there was a decrease in GSK-3ß phosphorylation in vessels from hypertensive rats (relative GSK-3ß phosphorylation: aortae, sham 0.767±0.153 versus DOCA 0.253±0.031; carotid arteries, sham 1.06±0.334 versus DOCA 0.125±0.081) (Figure 2).



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Figure 2. Immunoblot analysis of GSK-3ß phosphorylation in aortae (A) and carotid arteries (B) of normotensive and DOCA-salt hypertensive rats. C, Densitometric analysis of GSK-3ß phosphorylation (n=6) graphed as a relative phosphorylation per total GSK-3ß (mean±SEM). *P<0.05.

To confirm that the decreased GSK-3ß phosphorylation correlated with increased GSK-3 activity,15 we assessed the level of GSK-3 activity in arterial homogenates from DOCA-salt hypertensive and control rats. As expected, GSK3 activity was approximately twice as high in tissue homogenates from carotid arteries of DOCA-salt hypertensive animals when compared with control homogenates (sham 3532±438 versus DOCA 6543±566 cpm/µg protein/5 minutes) (Figure 3A). The GSK-3 inhibitor, SB415286, reduced GSK-3 related kinase activity in arterial homogenates at 1 µmol/L and, especially, at 10 µmol/L, confirming the specificity of this inhibitor in arterial tissue (Figure 3B).



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Figure 3. A, GSK-3 activity assessed in DOCA-salt hypertensive rat carotid arteries compared with normotensive controls (n=4). Data are expressed as cpm/µg protein/5 minutes (mean±SEM) and significance was determined using a one-way ANOVA (*P<0.05 versus sham control, **P<0.05 versus respective tissue controls). B, GSK-3 activity assay performed on tissue homogenates of normotensive rat aortae and carotid arteries in the presence and absence of SB415286 (1 µmol/L and 10 µmol/L) expressed as a percentage of control samples (mean±SEM, *P<0.05 versus respective tissue controls).

To further characterize the apparent dissociation of PI3K and GSK-3 activities in DOCA-salt vessels, we assessed the activity of signaling intermediates between PI3K and GSK-3. We previously reported that Akt Ser473 phosphorylation was decreased in vascular smooth muscle of hypertensive animals.5 Because activity of Akt is dependent on the phosphorylation state of both Ser473 and Thr308, we assessed the phosphorylation state of Akt Thr308 and found a 43.5±1.2% decrease in its phosphorylation in aortae from hypertensive animals (Figure 4A). In addition, we examined the phosphorylation of PDK1, which mediates PI3K-induced phosphorylation of Akt. There was no difference in PDK1 phosphorylation in DOCA-salt and sham vessels (relative PDK1 phosphorylation: sham 1.53± 0.23, DOCA 152±0.15) (Figure 4B).



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Figure 4. A, Immunoblot analysis of PDK phosphorylation in aortae of normotensive and DOCA-salt hypertensive rats. B, Immunoblot analysis of AktThr308 phosphorylation in aortae of normotensive and DOCA-salt hypertensive rats. Densitometric analysis is graphed as relative phosphorylation per total PDK or Akt protein, respectively. The number of animals is indicated on the graph, and the data are presented as mean±SEM. *P<0.05.

To determine whether increased GSK-3 activity contributes to enhanced reactivity of the hypertensive vessels, we assessed the effect of 2 GSK-3 specific inhibitors, SB415286 (1 µmol/L and 10 µmol/L) and SB216763 (1 µmol/L) (data not shown) on aortae and carotid arteries from normotensive and hypertensive animals. SB415286 had no effect on reactivity in the aortae at 1 µmol/L (-log EC50 values [mol/L]: DOCA -8.07±0.10 versus DOCASB415286 -7.87±0.07 and sham -7.70±0.10 versus shamSB415286 -7.53±0.06) but modestly attenuated reactivity at 10 µmol/L (-log EC50 values [mol/L]: DOCA -8.06±0.18 versus DOCASB415286 -7.72±0.16 and sham -7.91±0.14 versus shamSB415286 -797±0.21) of the hypertensive vessels at (Figure 5). Essentially no effects were seen in the carotid arteries incubated with SB415286 at 1 µmol/L (-log EC50 values [mol/L]: DOCA -8.06±0.16 versus DOCASB415286 -8.04±0.13 and sham -7.98±0.22 versus shamSB415286 -7.98±0.13) and 10 µmol/L (-log EC50 values [mol/L]: DOCA -7.84±0.11 versus DOCASB415286 -7.79±0.10 and sham -7.84±0.11 versus shamSB415286 -8.26±0.09) (Figure 6). These data suggest that increased GSK-3 activity may contribute modestly to the enhanced reactivity in DOCA-salt aortae but plays no role in the carotid artery reactivity.



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Figure 5. Effect of GSK-3 inhibitor SB415286 (top, 1 µmol/L; bottom, 10 µmol/L) on norepinephrine-induced contraction in aortae from normotensive and DOCA-salt hypertensive rats. Data are presented as a percentage of maximum norepinephrine-induced contraction (left) or as a percentage of the phenylephrine (PE) (10-5 mol/L) response (right) (mean±SEM).



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Figure 6. Effect of GSK-3 inhibitor SB415286 (10 µmol/L) on norepinephrine-induced contraction in carotid arteries from normotensive and DOCA-salt hypertensive rats. Data are presented as a percentage of maximum norepinephrine-induced contraction (left) or as a percentage of the phenylephrine (PE) (10-5 mol/L) response (right) (mean±SEM). *Sham vs shamSB; #DOCA vs DOCASB; $sham vs DOCA. P<0.05.


*    Discussion
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up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Recent results have shown that the enhanced contractile response to norepinephrine in DOCA-salt hypertensive arteries is due to enhanced PI3K activity.5 The current study addresses whether downstream kinases known to be regulated by PI3K, specifically PDK1, Akt, and GSK-3, are involved in this enhanced contractile response. Contrary to expectations, phosphorylation of 2 of these downstream kinases, Akt and GSK-3, was reduced, not enhanced, in DOCA-salt vessels. Besides suggesting a complex regulation of Akt and GSK-3 in vascular smooth muscle cells, these data support the hypothesis that PI3K enhances contractility through signaling pathways other than the Akt/GSK-3 pathway.

GSK-3ß has been shown to be an important signaling molecule in regulating glucose transport and glycolytic metabolism in a variety of tissues including vascular smooth muscle.15,16 Previous reports have demonstrated a significant decrease in both glucose transporter expression and glucose transport in vascular smooth muscle cells from aortae and carotid arteries of DOCA-salt hypertensive rats and that this impaired glycolytic metabolism contributes to the altered contractility profile in hypertension.14 Thus, we determined whether the surprising decrease in GSK-3 phosphorylation and the concomitant increase in activity contributed to the enhanced norepinephrine-induced contractions seen in the arteries from hypertensive animals.

Whereas the use of the GSK-3 inhibitors, SB415286 and SB216762, at a 1 µmol/L had no effect on the norepinephrine-induced contraction, SB415286 at 10 µmol/L demonstrated a relatively modest attenuation of the norepinephrine-induced reactivity in aortae from the hypertensive animals. Although these compounds have not been used previously to study the effects of GSK-3ß activity on arterial contractility, the 10 µmol/L dose appears to be the effective dose in in vivo preparations.17 While further experiments will be required to definitively assess the functional effects of increased GSK-3ß activity in hypertensive vessels, any effects of increased GSK-3 activity on contractility in hypertensive vessels would likely be independent of, and additive to, the well-documented effects of enhanced PI3K activity on arterial contractility.5

Perspectives
The surprising reduction in Akt and GSK-3ß phosphorylation in hypertensive aortae despite increased PI3K activity suggests a number of potential future lines of investigation. First, the dissociation between PI3K and Akt and GSK-3ß signaling found in DOCA-salt hypertensive arteries is quite unusual. The cellular mechanisms behind this dissociation have yet to be elucidated but may involve other vascular signaling pathways that are induced by DOCA-salt hypertension. Second, these data make very clear that the enhanced PI3K-associated arterial reactivity found in this model is not due to changes in Akt/GSK-3ß signaling. Finally, although enhanced GSK-3ß activity appears to play little direct role in vascular reactivity, it may participate in long-term modulation of hypertrophy in hypertensive vascular smooth muscle cells as it does in cardiac myocytes. Enhanced activity may protect against hypertrophy12 and may be an important counterbalance to hypertrophic stimuli in hypertension. Further augmentation of GSK-3 activity in vascular smooth muscle cells might prevent or reduce such changes in hypertension.


*    Acknowledgments
 
This work was supported by National Institutes of Health (NIH) grants RO1 HL 60156 and HL 65567 to F.C.B. and an institutional NIH predoctoral National Research Service Award (T32 GM08322) to R.D.L.

Received December 6, 2002; first decision December 31, 2002; accepted February 5, 2003.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Yang ZW, Wang J, Zheng T, Altura BT, Altura BM. Importance of PKC and PI3Ks in ethanol-induced contraction of cerebral arterial smooth muscle. Am J Physiol Heart Circ Physiol. 2001; 280: H2144–H2152.[Abstract/Free Full Text]
  2. Yang Z, Wang J, Altura BT, Altura BM. Extracellular magnesium deficiency induces contraction of arterial muscle: role of PI3-kinases and MAPK signaling pathways. Pflugers Arch. 2000; 439: 240–247.[CrossRef][Medline] [Order article via Infotrieve]
  3. Komalavilas P, Mehta S, Wingard CJ, Dransfield DT, Bhalla J, Woodrum JE, Molinaro JR, Brophy CM. PI3-kinase/Akt modulates vascular smooth muscle tone via cAMP signaling pathways. J Appl Physiol. 2001; 91: 1819–1827.[Abstract/Free Full Text]
  4. Ibitayo AI, Tsunoda Y, Nozu F, Owyang C, Bitar KN. Src kinase and PI3-kinase as transduction pathway in ceramide-induced contraction of colonic smooth muscle. Am J Physiol. 1998; 275: G705–G711.[Medline] [Order article via Infotrieve]
  5. Northcott CA, Poy MN, Najjar SM, Watts SW. Phosphoinositide 3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of deoxycorticosterone acetate-salt hypertensive rats. Circ Res. 2002; 91: 360–369.[Abstract/Free Full Text]
  6. Ahmad Z, Camici M, DePaoli-Roach AA, Roach PJ. Glycogen synthase kinases. Classification of a rabbit liver casein and glycogen synthase kinase (casein kinase-1) as a distinct enzyme. J Biol Chem. 1984; 259: 3420–3428.[Abstract/Free Full Text]
  7. Woodgett JR. Judging a protein by more than its name: GSK-3. Sci STKE. 2001; RE12.
  8. Cohen P, Frame S. The renaissance of GSK3. Nat Rev Mol Cell Biol. 2001; 2: 769–776.[CrossRef][Medline] [Order article via Infotrieve]
  9. Stambolic V, Woodgett JR. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J. 1994; 303: 701–704.[Medline] [Order article via Infotrieve]
  10. Moule SK, Welsh GI, Edgell NJ, Foulstone EJ, Proud CG, Denton RM. Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms. J Biol Chem. 1997; 272: 7713–7719.[Abstract/Free Full Text]
  11. Hu ZW, Shi XY, Lin RZ, Hoffman BB. Alpha1 adrenergic receptors activate phosphatidylinositol 3-kinase in human vascular smooth muscle cells. Role in mitogenesis. J Biol Chem. 1996; 271: 8977–8982.[Abstract/Free Full Text]
  12. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN. Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2002; 99: 907–912.[Abstract/Free Full Text]
  13. Florian JA, Watts SW. Epidermal growth factor: a potent vasoconstrictor in experimental hypertension. Am J Physiol. 1999; 276: H976–H983.[Medline] [Order article via Infotrieve]
  14. Atkins KB, Johns D, Watts S, Webb RC, Brosius FC III. Decreased vascular glucose transporter expression and glucose uptake in DOCA-salt hypertension. J Hypertens. 2001; 19: 1581–1587.[CrossRef][Medline] [Order article via Infotrieve]
  15. Loberg RD, Vesely E, Brosius FC3rd. Enhanced glycogen synthase kinase-3ß activity mediates hypoxia-induced apoptosis of vascular smooth muscle cells and is prevented by glucose transport and metabolism. J Biol Chem. 2002: 277: 41667–41673.[Abstract/Free Full Text]
  16. Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, Birnbaum MJ. The role of glycogen synthase kinase 3ß in insulin-stimulated glucose metabolism. J Biol Chem. 1999; 274: 17934–17940.[Abstract/Free Full Text]
  17. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 2000; 10: 793–803.



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