Circulation Research. 2004;94:362-369
Published online before print December 11, 2003, doi: 10.1161/01.RES.0000112406.27800.6F
Published online before print December 11, 2003, doi: 10.1161/01.RES.0000112406.27800.6F
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Cellular Biology |
Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis
From the Center for Cardiovascular Research and Department of Medicine, University of Rochester, Rochester, NY.
Correspondence to Bradford C. Berk, MD, PhD, Cardiology Unit, Box 679, 601 Elmwood Ave, Rochester, NY 14642. E-mail Bradford_Berk{at}urmc.rochester.edu
Blood flow that is steady and laminar is known to be atheroprotective. One likely mechanism is enhanced endothelial cell (EC) survival. Because the mitogen-activated protein kinases (MAPKs) are known regulators of cell survival, we investigated the role of Big MAPK-1 (BMK1 or ERK5), which is potently stimulated by fluid shear stress. To activate BMK1, we overexpressed constitutively active (CA)-MEK5 in bovine lung microvascular ECs (BLMECs). Cell apoptosis was induced by growth factor deprivation (0% serum for 24 hours). Analysis of cell viability with MTT assay showed that activation of BMK1 by CA-MEK5 significantly improved cell viability from 48% to 87% and decreased apoptotic cells from 49% to 10%. Growth factor deprivation induced caspase-3 activity 5.2-fold, which was inhibited (
60%) by CA-MEK5 overexpression. In contrast, inhibiting BMK1 activity by overexpressing dominant-negative BMK1 (DN-BMK1) stimulated apoptosis in BLMECs. Steady laminar fluid shear stress inhibited BLMEC apoptosis, and this protective effect was also reduced significantly by overexpressing DN-BMK1. Analysis of antiapoptotic mechanisms showed that both shear stress and CA-MEK5 stimulated phosphorylation of Bad on Ser112 and Ser136, whereas DN-BMK1 inhibited phosphorylation. Phosphorylation of Bad induced by BMK1 activation was independent of Akt, PKA, or p90RSK kinase activity. These results suggest that BMK1 activation by steady laminar flow is atheroprotective by inhibiting EC apoptosis via phosphorylation of Bad.
Key Words: apoptosis • big mitogen-activated protein kinase • Bad
This article has been cited by other articles:
 |
|
 |
|
  D. Spiering, M. Schmolke, N. Ohnesorge, M. Schmidt, M. Goebeler, J. Wegener, V. Wixler, and S. Ludwig MEK5/ERK5 Signaling Modulates Endothelial Cell Migration and Focal Contact Turnover J. Biol. Chem., September 11, 2009; 284(37): 24972 - 24980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Carter, R. A. Cosgrove, I. Gonzalez, J. H. Eisemann, F. A. Lovett, L. J. Cobb, and J. M. Pell MEK5 and ERK5 are mediators of the pro-myogenic actions of IGF-2 J. Cell Sci., September 1, 2009; 122(17): 3104 - 3112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ishizawa, N. Dorjsuren, Y. Izawa-Ishizawa, R. Sugimoto, Y. Ikeda, Y. Kihira, K. Kawazoe, S. Tomita, K. Tsuchiya, K. Minakuchi, et al. Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration J. Endocrinol., August 1, 2009; 202(2): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Terada What Underlies Endothelial Shear Sensing? The Matrix, of Course Circ. Res., September 12, 2008; 103(6): 562 - 564. [Full Text] [PDF]
|
|
|
|
|
|
A. R. Kinderlerer, F. Ali, M. Johns, E. A. Lidington, V. Leung, J. J. Boyle, S. S. Hamdulay, P. C. Evans, D. O. Haskard, and J. C. Mason KLF2-dependent, Shear Stress-induced Expression of CD59: A NOVEL CYTOPROTECTIVE MECHANISM AGAINST COMPLEMENT-MEDIATED INJURY IN THE VASCULATURE J. Biol. Chem., May 23, 2008; 283(21): 14636 - 14644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Berk Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells Circulation, February 26, 2008; 117(8): 1082 - 1089. [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Potthoff and E. N. Olson MEF2: a central regulator of diverse developmental programs Development, December 1, 2007; 134(23): 4131 - 4140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Garin, J.-i. Abe, A. Mohan, W. Lu, C. Yan, A. C. Newby, A. Rhaman, and B. C. Berk Flow Antagonizes TNF-{alpha} Signaling in Endothelial Cells by Inhibiting Caspase-Dependent PKC{zeta} Processing Circ. Res., July 6, 2007; 101(1): 97 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhande and A. Karsan Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-{kappa}B-independent upregulation of Bcl-xL Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2467 - H2474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yan, C. L. Miller, and J.-i. Abe Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart Circ. Res., March 2, 2007; 100(4): 489 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yan, B. Ding, T. Shishido, C.-H. Woo, S. Itoh, K.-I. Jeon, W. Liu, H. Xu, C. McClain, C. A. Molina, et al. Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop Circ. Res., March 2, 2007; 100(4): 510 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zhuang and R. G. Schnellmann A Death-Promoting Role for Extracellular Signal-Regulated Kinase J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 991 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sato, K. Harada, S. Furubo, K. Kizawa, T. Sanzen, M. Yasoshima, S. Ozaki, K. Isse, M. Sasaki, and Y. Nakanuma Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib Am. J. Pathol., October 1, 2006; 169(4): 1238 - 1250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. R. Sastry, Y. Karpova, and G. Kulik Epidermal Growth Factor Protects Prostate Cancer Cells from Apoptosis by Inducing BAD Phosphorylation via Redundant Signaling Pathways J. Biol. Chem., September 15, 2006; 281(37): 27367 - 27377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Schweppe, T. H. Cheung, and N. G. Ahn Global Gene Expression Analysis of ERK5 and ERK1/2 Signaling Reveals a Role for HIF-1 in ERK5-mediated Responses J. Biol. Chem., July 28, 2006; 281(30): 20993 - 21003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wu, A. Kajdacsy-Balla, E. Strawn, Z. Basir, G. Halverson, P. Jailwala, Y. Wang, X. Wang, S. Ghosh, and S.-W. Guo Transcriptional Characterizations of Differences between Eutopic and Ectopic Endometrium Endocrinology, January 1, 2006; 147(1): 232 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Sohn, D. Li, L. K. Lee, and A. Winoto Transcriptional Regulation of Tissue-Specific Genes by the ERK5 Mitogen-Activated Protein Kinase Mol. Cell. Biol., October 1, 2005; 25(19): 8553 - 8566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Cai Hydrogen peroxide regulation of endothelial function: Origins, mechanisms, and consequences Cardiovasc Res, October 1, 2005; 68(1): 26 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Watanabe, J. Suzuki, H. Yamawaki, V. K. Sharma, S.-S. Sheu, and B. C. Berk Losartan Metabolite EXP3179 Activates Akt and Endothelial Nitric Oxide Synthase via Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells: Angiotensin II Type 1 Receptor-Independent Effects of EXP3179 Circulation, September 20, 2005; 112(12): 1798 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-k. Tai, Q. Zheng, S. Pan, Z.-G. Jin, and B. C. Berk Flow Activates ERK1/2 and Endothelial Nitric Oxide Synthase via a Pathway Involving PECAM1, SHP2, and Tie2 J. Biol. Chem., August 19, 2005; 280(33): 29620 - 29624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Itoh, S. Lemay, M. Osawa, W. Che, Y. Duan, A. Tompkins, P. S. Brookes, S.-S. Sheu, and J.-i. Abe Mitochondrial Dok-4 Recruits Src Kinase and Regulates NF-{kappa}B Activation in Endothelial Cells J. Biol. Chem., July 15, 2005; 280(28): 26383 - 26396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Pi, G. Garin, L. Xie, Q. Zheng, H. Wei, J.-i. Abe, C. Yan, and B. C. Berk BMK1/ERK5 Is a Novel Regulator of Angiogenesis by Destabilizing Hypoxia Inducible Factor 1{alpha} Circ. Res., June 10, 2005; 96(11): 1145 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Carvajal-Vergara, S. Tabera, J. C. Montero, A. Esparis-Ogando, R. Lopez-Perez, G. Mateo, N. Gutierrez, M. Parmo-Cabanas, J. Teixido, J. F. San Miguel, et al. Multifunctional role of Erk5 in multiple myeloma Blood, June 1, 2005; 105(11): 4492 - 4499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, A. J. Merritt, J. Seyfried, C. Guo, E. S. Papadakis, K. G. Finegan, M. Kayahara, J. Dixon, R. P. Boot-Handford, E. J. Cartwright, et al. Targeted Deletion of mek5 Causes Early Embryonic Death and Defects in the Extracellular Signal-Regulated Kinase 5/Myocyte Enhancer Factor 2 Cell Survival Pathway Mol. Cell. Biol., January 1, 2005; 25(1): 336 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Akaike, W. Che, N.-L. Marmarosh, S. Ohta, M. Osawa, B. Ding, B. C. Berk, C. Yan, and J.-i. Abe The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor {gamma}1 (PPAR{gamma}1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPAR{gamma}1 Transcriptional Activation: Involvement in Flow-Induced PPAR{gamma} Activation in Endothelial Cells Mol. Cell. Biol., October 1, 2004; 24(19): 8691 - 8704. [Abstract] [Full Text] [PDF]
|
|