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1 Department of Cardiology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
2 Department of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
3 Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: jli{at}BIDMC.harvard.edu.
There is increasing evidence that Cyclooxygenase-2 (COX-2) possess both angiogenic and cardioprotective properties. We examined the effects of hypoxic-cardiac myocytes (H9c2) 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. The HMCM induced a transient increase of COX-2 mRNA expression at 1 and 3 hours, without affecting COX-1 mRNA level. A similar effect also observed in HMCM from cultured primary cardiac myocytes (Rat neonatal cardiac myocytes, RNCM). 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
(3.93±0.89 fold), slightly increased by TNF-
, but not by FGF2, IGF-1 or PDGFs. Analysis of proteins secreted in HMCM showed the increased levels of VEGF but not IL-1 or TNF-. 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 by prolonging COX-2 mRNA half-life. Furthermore, staurosporine, a non-selective PKC inhibitor, prevented the induction of VEGF by hypoxia. Both selective PKC , 1 inhibitor and iNOS 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 the 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
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