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Circulation Research. 2003
Published online before print December 11, 2003, doi: 10.1161/01.RES.0000112406.27800.6F
A more recent version of this article appeared on February 20, 2004
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Submitted on November 22, 2002
Revised on November 17, 2003
Accepted on December 12, 2003

Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis

Xinchun Pi ; Chen Yan ; and Bradford C. Berk *

From the Center for Cardiovascular Research and Department of Medicine, University of Rochester, Rochester, NY.

* To whom correspondence should be addressed. 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 ({approx}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




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