Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 24, Issue 12, Pages 2238-2244Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000147894.22300.4c
Keywords
angiogenesis; endothelium; nitric oxide; heat shock protein; protein kinase Akt
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Funding
- NHLBI NIH HHS [R01 HL052233-06, R01 HL052233, R01 HL052233-05, HL70274, P01 HL048743-120008, R01 HL070274, P01 HL048743, R01 HL070274-02, R01 HL070274-01] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062729-01A1, DK62729, R01 DK062729] Funding Source: Medline
- NINDS NIH HHS [P01 NS010828-330036, P50 NS010828, P50 NS010828-290036, P01 NS010828] Funding Source: Medline
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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.
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