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首页> 外文期刊>American Journal of Physiology >Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF.
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Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF.

机译：缺氧诱导内皮细胞中的心肌细胞依赖性COX-2调节：VEGF的作用。

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摘要

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-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.
机译：越来越多的证据表明，环氧合酶（COX）-2同时具有血管生成和心脏保护特性。我们检查了缺氧心肌细胞（H9c2细胞）对人脐静脉内皮细胞（HUVECs）中COX-2表达的影响，以确定参与COX-2调控的途径。将来自缺氧（<1％O2）心肌细胞（HMCM）或常氧性心肌细胞（21％O2）的培养基添加到HUVEC培养物中。 HMCM在1和3 h诱导COX-2 mRNA表达瞬时增加，而不影响COX-1 mRNA水平。在HMCM中，从培养的原代心肌细胞（大鼠新生心肌细胞）中也观察到了类似的效果。 COX-2 mRNA的增加与COX-2蛋白表达的时间依赖性增加有关。 VEGF（4.86 +/- 1.03倍）和IL-1beta（3.93 +/- 0.89倍）显着诱导COX-2，而TNF-alpha略有增加，但FGF2，IGF-1或PDGF则没有。对HMCM中分泌的蛋白质的分析显示，VEGF水平升高，但IL-1 beta或TNF-α水平没有升高。 HMCM诱导的COX-2表达受到抗VEGF中和抗体的抑制。 VEGF通过增加COX-2转录和延长COX-2 mRNA半衰期来诱导内皮细胞COX-2表达。此外，星形孢菌素（一种非选择性PKC抑制剂）可防止缺氧诱导VEGF。选择性PKC-α和-β抑制剂以及可诱导的一氧化氮合酶（NOS）抑制剂均降低了HMCM和VEGF对COX-2的诱导作用。最后，HMCM诱导的COX-2上调伴随PGI2和PGE2上调。这些结果表明，VEGF是低氧肌细胞产生的主要因子之一，其负责诱导内皮细胞COX-2表达。此过程可能涉及PKC和NOS途径。我们的发现对缺血性心脏病中CO​​X-2的心脏保护具有重要意义。

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