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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2238.)
© 2004 American Heart Association, Inc.

Vascular Biology

Induction of Angiogenesis by Heat Shock Protein 90 Mediated by Protein Kinase Akt and Endothelial Nitric Oxide Synthase

Jianxin Sun; James K. Liao

From Vascular Medicine Research Unit (J.S., J.K.L.), Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass; and the Department of Pharmacology (J.S.), Second Military Medical University, Shanghai, China.

Correspondence to James K. Liao, Brigham & Women’s Hospital, 65 Landsdowne Street, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu

Objective— A specific inhibitor of heat shock protein 90 (Hsp90), 17-AAG, has been shown to inhibit tumor growth through cell cycle arrest, differentiation, or apoptosis. Because angiogenesis is important for tumor growth, we hypothesize that inhibition of angiogenesis by 17-AAG may mediate some of its antitumor effects.

Methods and Results— Because protein kinase Akt and endothelial nitric oxide synthase (eNOS) are critical for angiogenesis, we studied the effects of 17-AAG on the phosphorylation and expression of Akt and eNOS in human umbilical vein endothelial cells. In a concentration- and time-dependent manner, inhibition of Hsp90 by 17-AAG decreased Akt and eNOS expression by 74% and 81%, respectively. Inhibition of eNOS expression by 17-AAG occurred at the transcriptional level as determined by eNOS promoter activity and nuclear run-on assay. Furthermore, treatment with 17-AAG decreased basal and vascular endothelial growth factor-stimulated Akt and eNOS phosphorylation. This corresponded with decreased NO production and inhibition of endothelial cell migration and angiogenesis. The anti-angiogenic effect of 17-AAG was partially reversed by the NO donor, SNAP.

Conclusions— These findings indicate that Hsp90 is important not only for Akt and eNOS phosphorylation but also for eNOS gene transcription and suggests that Hsp90 may be a novel target for anti-angiogenic therapy.

We showed that inhibition of Hsp90 leads not only to decreased Akt and eNOS phosphorylation but also to decreased eNOS gene transcription. This correlated with decrease VEGF-induced endothelial cell migration and angiogenesis. These findings indicate that inhibition of Hsp90 may be an important target for antitumor and anti-angiogenesis therapy.

Key Words: angiogenesis • endothelium • nitric oxide • heat shock protein • protein kinase Akt

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