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(Circulation. 2004;109:1660-1667.)
© 2004 American Heart Association, Inc.

Basic Science Reports

PR39 Inhibits Apoptosis in Hypoxic Endothelial Cells

Role of Inhibitor Apoptosis Protein-2

Jiaping Wu, MD; Cherie Parungo, MD^*; Guifu Wu, MD, PhD^*; Peter M. Kang, MD; Roger J. Laham, MD; Frank W. Sellke, MD; Michael Simons, MD; Jian Li, MD, PhD

From the Angiogenesis Research Center, Divisions of Cardiology (J.W., C.P., G.W., P.M.K., R.J.L., J.L.) and Cardiothoracic Surgery (F.W.S.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass, and Section of Cardiology, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School, Hanover, NH (M.S.).

Correspondence to Jian Li, MD, PhD, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215. E-mail jli{at}bidmc.harvard.edu

Received March 7, 2003; de novo received October 20, 2003; revision received December 15, 2003; accepted December 30, 2003.

Background— PR39 is a proline- and arginine-rich peptide implicated in wound healing and myocardial ischemia protection. To determine the potential mechanisms of PR39 in ischemia, we examined the role of PR39 in hypoxia-induced apoptosis in vascular endothelial cells.

Methods and Results— Hypoxia results in an increase of apoptosis in bovine aortic endothelial cells (BAECs), as determined by terminal deoxynucleotidyl transferase–mediated dUTP biotin nick-end labeling (TUNEL) analysis and caspase-3 activity. Hypoxia induced 66.2±2.7% TUNEL-positive cells, whereas in the presence of synthesized PR39 peptide, TUNEL-positive cells were reduced to 29.6±1.9% (P<0.05). After 24 hours of hypoxia, the addition of PR39 reduced caspase-3 activity to 3.17±0.47 pMol/min from 10.52±0.55 pMol/min in hypoxic BAECs. Moreover, PR39 increased inhibitor of apoptosis protein-2 (IAP-2) gene and protein expression by 3-fold in a time- and dose-dependent manner. The induction of IAP-2 by PR39 conferred an increase in IAP-2 gene transcription and IAP-2 mRNA stability. Furthermore, inhibiting IAP-2 with second mitochondria-derived activator of caspase (Smac) and with small interfering RNA targeting IAP-2 abrogated the ability of PR39 to reduce caspase-3 activity.

Conclusions— We provide the first direct evidence for PR39 as an antiapoptotic factor in endothelial cells during hypoxia. These data suggest that PR39 inhibits hypoxia-induced apoptosis and decreases caspase-3 activity in endothelial cells through an increase of IAP-2 expression.

Key Words: peptides • hypoxia • apoptosis • cells, endothelial

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