Author/Editor     Wu, Guifu; Mannam, Arjuna P.; Wu, Jiaping; Kirbiš, Simona; Shie, Jue-Lon; Chen, Christopher; Laham, Roger J.; Sellke, Frank W.; Li, Jian
Title     Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF
Type     članek
Vol. and No.     Letnik 285, št. 6
Publication year     2003
Volume     str. H2420-H2429
ISSN     American journal of physiology. Heart and circulatory physiology Med
Language     eng
Abstract     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 atransient 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-1beta (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.
Descriptors     Anoxia
Anoksija
Myocardial Ischemia
Miokardialna ishemija
Vascular Endothelial Growth Factor A
Vaskularni endotelni rastni faktor A
Endothelial Cells
Endotelijske celice
Gene Expression Regulation, Enzymologic
Gensko izražanje, encimska reakcija
Isoenzymes
Izoencimi
Umbilical Veins
Popkovnične vene
Signal Transduction
Signal, prenos
Myocytes, Cardiac
Srčni miociti
Cyclooxygenase 2
Ciklooksigenaza 2
Rats
Podgane
Metabolism
Metabolizem
Metabolism
Metabolizem
Cytology
Enzymology
Citologija
Enzimologija
Genetics
Metabolism
Genetika
Metabolizem
Cytology
Citologija
Physiology
Fiziologija