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J. Biol. Chem., Vol. 282, Issue 44, 32288-32297, November 2, 2007

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A Protein Kinase C-Anti-apoptotic Kinase Signaling Complex Protects Human Vascular Endothelial Cells against Apoptosis through Induction of Bcl-2^*

Rivka Steinberg, Olivier A. Harari, Elaine A. Lidington, Joseph J. Boyle, Mahrokh Nohadani, Allen M. Samarel^¶, Motoi Ohba^||, Dorian O. Haskard, and Justin C. Mason¹

From the Bywaters Center for Vascular Inflammation and Histopathology Section, Imperial College London, Hammersmith Hospital, London, W12 ONN United Kingdom, ^¶The Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, and ^||Institute of Molecular Oncology, Showa University, Shinagawa, Tokyo 142-8555, Japan

Endothelial cell apoptosis is associated with vascular injury and predisposes to atherogenesis. Endothelial cells express anti-apoptotic genes including Bcl-2, Bcl-X_L and survivin, which also contribute to angiogenesis and vascular remodeling. We report a central role for protein kinase C (PKC) in the regulation of Bcl-2 expression and cytoprotection of human vascular endothelium against apoptosis. Using myristoylated inhibitory peptides, a predominant role for PKC in vascular endothelial growth factor-mediated endothelial resistance to apoptosis was revealed. Immunoblotting of endothelial cells infected with an adenovirus expressing a constitutively active form of PKC (Adv-PKC-CA) or control Adv--galactosidase demonstrated a 3-fold, PKC-dependent increase in Bcl-2 expression, with no significant change in Bcl-X_L, Bad, Bak, or Bax. The induction of Bcl-2 inhibited apoptosis induced by serum starvation or etoposide, and PKC activation attenuated etoposide-induced caspase-3 cleavage. The functional role of Bcl-2 was confirmed with Bcl-2 antagonist HA-14-1. Inhibition of phosphoinositide 3-kinase attenuated vascular endothelial growth factor-induced protection against apoptosis, and this was rescued by overexpression of constitutively active PKC, suggesting PKC acts downstream of phosphoinositide 3-kinase. Co-immunoprecipitation studies demonstrated a physical interaction between PKC and Akt, which resulted in formation of a signaling complex, leading to optimal induction of Bcl-2. This study reveals a pivotal role for PKC in endothelial cell cytoprotection against apoptosis. We demonstrate that PKC forms a signaling complex and acts co-operatively with Akt to protect human vascular endothelial cells against apoptosis through induction of the anti-apoptotic protein Bcl-2 and inhibition of caspase-3 cleavage.

Received for publication, May 15, 2007 , and in revised form, August 16, 2007.

^* This work was funded through Arthritis Research Campaign Senior Fellowship 13616 (to J. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Bywaters Center for Vascular Inflammation, Imperial College London, Hammersmith Hospital, Du Cane Rd., London, W12 ONN, UK. Tel.: 44-20-383-1622; Fax: 44-20-383-1640; E-mail: justin.mason{at}imperial.ac.uk.

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