Hsp90 mediates the balance of nitric oxide and superoxide anion in the lungs of rats with acute pulmonary thromboembolism

Acute pulmonary thromboembolism (PTE) can result in serious vascular responses. The association of heat shock protein 90 (Hsp90) with endothelial nitric oxide synthase (eNOS), which generates nitric oxide (NO) and superoxide anion (O−2), is a critical mechanism on regulating vessel homeostasis. In this study, the role of Hsp90 association with eNOS in the balance of NO and O−2 was examined in PTE rat model. PTE rats model was induced by intrajugular injection of autologous blood clots (0.04 g/kg), lung homogenate was collected at appointed time length to assess NO production and O−2 production. The interaction of Hsp90 and eNOS protein in every group was detected. Treatment of PTE model rats with geldanamycin, a commonly used Hsp90 inhibitor, augmented eNOS phosphorylation at Thr-495, depressing eNOS activity. Together with the increase of NO production in lung homogenate of PTE rats at 1 h and its maximum reached at 3 d, geldanamycin treatment significantly attenuated the production of NO but augmented the production of O−2 in the lungs of rats after PTE at indicated time length. These results suggest that geldanamycin may enhance eNOS phosphorylation at Thr-495 by inhibiting Hsp90, Hsp90 uncoupling eNOS protein results in increased eNOS-dependent O−2 production.