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Am J Physiol Heart Circ Physiol 285: H2420-H2429, 2003. First published July 24, 2003; doi:10.1152/ajpheart.00187.2003
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Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF

Guifu Wu,1 Arjuna P. Mannam,1 Jiaping Wu,1 Simona Kirbis,1 Jue-Lon Shie,1 Christopher Chen,2 Roger J. Laham,1 Frank W. Sellke,3 and Jian Li1

1Angiogenesis Research Center, Division of Cardiology, 2Department of Medicine, 3Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts 02215

Submitted 14 April 2003 ; accepted in final form 21 July 2003

There is increasing evidence that cyclooxygenase (COX)-2 possess both angiogenic and cardioprotective properties. We examined the effects of hypoxic cardiac myocytes (H9c2 cells) on COX-2 expression in human umbilical vein endothelial cells (HUVECs) to determine the pathway involved in COX-2 regulation. The medium from hypoxic (<1% O2) cardiac myocytes (HMCM) or normoxic cardiac myocytes (21% O2) was added to HUVEC cultures. HMCM induced a transient increase of COX-2 mRNA expression at 1 and 3 h without affecting the COX-1 mRNA level. A similar effect also observed in HMCM from cultured primary cardiac myocytes (rat neonatal cardiac myocytes). The increased COX-2 mRNA was associated with a time-dependent increase in COX-2 protein expression. COX-2 was significantly induced by VEGF (4.86 ± 1.03-fold) and IL-1{beta} (3.93 ± 0.89-fold) and slightly increased by TNF-{alpha} but not by FGF2, IGF-1, or PDGFs. Analysis of proteins secreted in HMCM showed increased levels of VEGF but not IL-1{beta} or TNF-{alpha}. The HMCM-induced COX-2 expression was inhibited by the addition of an anti-VEGF neutralizing antibody. VEGF induced endothelial cell COX-2 expression by both increasing COX-2 transcription and prolonging the COX-2 mRNA half-life. Furthermore, staurosporine, a nonselective PKC inhibitor, prevented the induction of VEGF by hypoxia. Both a selective PKC-{alpha} and -{beta} inhibitor and an inducible nitric oxide synthase (NOS) inhibitor decreased the induction of COX-2 by HMCM and VEGF. Finally, HMCM-induced upregulation of COX-2 was accompanied by upregulation of PGI2 and PGE2. These results suggest that VEGF is one of the principal factors produced by hypoxic myocytes that is responsible for the induction of endothelial cell COX-2 expression. This process likely involves both PKC and NOS pathways. Our findings have important implications regarding the cardiac protection of COX-2 in ischemic heart disease.

cyclooxygenase-2; vascular endothelial growth factor; cardiac myocytes


Address for reprint requests and other correspondence: J. Li, Angiogenesis Research Center, Div. of Cardiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave., Boston, MA 02215 (E-mail: jli{at}BIDMC.harvard.edu).




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