Published online before print June 20, 2005, doi: 10.1161/CIRCULATIONAHA.105.546812
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2005;111:3473-3480.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase
From the Evans Memorial Department of Medicine (E.S., E.A., J.F.K.), Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass; and the Vascular Research Laboratory (M.-H.Z.), Graduate School of Medicine, University of Tennessee, Knoxville.
Correspondence to John F. Keaney, Jr, MD, Boston University School of Medicine, Whitaker Cardiovascular Institute, 715 Albany St, Boston, MA 02118. E-mail jkeaney{at}bu.edu
Received March 2, 2005; revision received March 17, 2005; accepted March 21, 2005.
Background— Estradiol activates endothelial nitric oxide synthase (eNOS) by mechanisms that involve estrogen receptor-
(ER), protein kinase B/Akt, mitogen-activated protein kinases, and heat shock protein 90 (HSP90). Recently, AMP-activated protein kinase (AMPK), an enzyme that plays a crucial role in cellular adaptation to metabolic stress, has been implicated in physiological eNOS activation by the hormones adiponectin and insulin. We therefore investigated whether AMPK is activated by estradiol in endothelial cells and plays a role in estradiol-induced eNOS activation.
Methods and Results— Porcine aortic endothelial cells exhibited time- and concentration-dependent AMPK activation as determined by phosphorylation of AMPK and its downstream target acetyl coenzyme A carboxylase in response to estradiol (1 nmol/L to 10 µmol/L, 1 to 30 minutes). AMPK activation by estradiol was independent of both AMP levels and ER but required estradiol conversion to its catechol metabolites. Estradiol treatment increased eNOS catalytic activity, an effect that was largely reversed when endothelial cells were infected with an AMPK dominant-negative adenovirus. However, inhibition of AMPK did not alter estradiol-induced eNOS phosphorylation at serine 1177 or threonine 495 but decreased eNOS interaction with HSP90. Consistent with this observation, blood vessels from 1-AMPK-null mice exhibited defective eNOS-mediated NO production in response to estradiol.
Conclusions— Taken together, these data indicate that AMPK activity is essential for estradiol-induced eNOS activation via the promotion of eNOS interaction with HSP90. These data point to a novel role for AMPK in modulating endothelial cell NO bioactivity and HSP90 function.
Key Words: endothelium • nitric oxide synthase • signal transduction • adenylate kinase • heat shock proteins
This article has been cited by other articles:
 |
|
 |
|
  G. Han, H. Ma, R. Chintala, D. J. R. Fulton, S. A. Barman, and R. E. White Essential Role of the 90-Kilodalton Heat Shock Protein in Mediating Nongenomic Estrogen Signaling in Coronary Artery Smooth Muscle J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 850 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, Y. Huang, K. S.L. Lam, Y. Li, W. T. Wong, H. Ye, C.-W. Lau, P. M. Vanhoutte, and A. Xu Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase Cardiovasc Res, June 1, 2009; 82(3): 484 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zerr-Fouineau, M. Jourdain, C. Boesch, M. Hecker, C. Bronner, and V. B. Schini-Kerth Certain Progestins Prevent the Enhancing Effect of 17{beta}-Estradiol on NO-Mediated Inhibition of Platelet Aggregation by Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2009; 29(4): 586 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schulz, S. Schuhmacher, and T. Munzel When Metabolism Rules Perfusion: AMPK-Mediated Endothelial Nitric Oxide Synthase Activation Circ. Res., February 27, 2009; 104(4): 422 - 424. [Full Text] [PDF]
|
|
|
|
|
|
Z. Chen, I-C. Peng, W. Sun, M.-I Su, P.-H. Hsu, Y. Fu, Y. Zhu, K. DeFea, S. Pan, M.-D. Tsai, et al. AMP-Activated Protein Kinase Functionally Phosphorylates Endothelial Nitric Oxide Synthase Ser633 Circ. Res., February 27, 2009; 104(4): 496 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schulz, J. Dopheide, S. Schuhmacher, S. R. Thomas, K. Chen, A. Daiber, P. Wenzel, T. Munzel, and J. F. Keaney Jr Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction Circulation, September 23, 2008; 118(13): 1347 - 1357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. C. Levine, G. K. Li, and T. Michel Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells: EVIDENCE FOR AN AMPK -> Rac1 -> Akt -> ENDOTHELIAL NITRIC-OXIDE SYNTHASE PATHWAY J. Biol. Chem., July 13, 2007; 282(28): 20351 - 20364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K.Y. Cheng, K. S.L. Lam, Y. Wang, Y. Huang, D. Carling, D. Wu, C. Wong, and A. Xu Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells Diabetes, May 1, 2007; 56(5): 1387 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Monsalve, P. J. Oviedo, M. A. Garcia-Perez, J. J. Tarin, A. Cano, and C. Hermenegildo Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells Cardiovasc Res, January 1, 2007; 73(1): 66 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Sun, T.-S. Lee, M. Zhu, C. Gu, Y. Wang, Y. Zhu, and J. Y-J. Shyy Statins Activate AMP-Activated Protein Kinase In Vitro and In Vivo Circulation, December 12, 2006; 114(24): 2655 - 2662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. W. Dolinsky and J. R. B. Dyck Role of AMP-activated protein kinase in healthy and diseased hearts Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2557 - H2569. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Turgeon, M. C. Carr, P. M. Maki, M. E. Mendelsohn, and P. M. Wise Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies Endocr. Rev., October 1, 2006; 27(6): 575 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Li, D. L. Coven, E. J. Miller, X. Hu, M. E. Young, D. Carling, A. J. Sinusas, and L. H. Young Activation of AMPK {alpha}- and {gamma}-isoform complexes in the intact ischemic rat heart Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1927 - H1934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Joy, R. C. M. Siow, D. J. Rowlands, M. Becker, A. W. Wyatt, P. I. Aaronson, C. W. Coen, I. Kallo, R. Jacob, and G. E. Mann The Isoflavone Equol Mediates Rapid Vascular Relaxation: Ca2+-INDEPENDENT ACTIVATION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE/Hsp90 INVOLVING ERK1/2 AND Akt PHOSPHORYLATION IN HUMAN ENDOTHELIAL CELL J. Biol. Chem., September 15, 2006; 281(37): 27335 - 27345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Stahmann, A. Woods, D. Carling, and R. Heller Thrombin Activates AMP-Activated Protein Kinase in Endothelial Cells via a Pathway Involving Ca2+/Calmodulin-Dependent Protein Kinase Kinase {beta}. Mol. Cell. Biol., August 1, 2006; 26(16): 5933 - 5945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. D'Eon, S. C. Souza, M. Aronovitz, M. S. Obin, S. K. Fried, and A. S. Greenberg Estrogen Regulation of Adiposity and Fuel Partitioning: EVIDENCE OF GENOMIC AND NON-GENOMIC REGULATION OF LIPOGENIC AND OXIDATIVE PATHWAYS J. Biol. Chem., October 28, 2005; 280(43): 35983 - 35991. [Abstract] [Full Text] [PDF]
|
|