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2016 ; 7
(34
): 54263-54273
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Inhibition of heat shock protein 90 improves pulmonary arteriole remodeling in
pulmonary arterial hypertension
#MMPMID27472464
Wang GK
; Li SH
; Zhao ZM
; Liu SX
; Zhang GX
; Yang F
; Wang Y
; Wu F
; Zhao XX
; Xu ZY
Oncotarget
2016[Aug]; 7
(34
): 54263-54273
PMID27472464
show ga
While the molecular chaperone heat shock protein 90 (HSP90) is involved in a
multitude of physiological and pathological processes, its role relating to
pulmonary arterial hypertension (PAH) remains unclear. In the present study, we
investigated the effect in which HSP90 improves pulmonary arteriole remodeling,
and explored the therapeutic utility of targeting HSP90 as therapeutic drug for
PAH. By Elisa and immunohistochemistry, HSP90 was found to be increased in both
plasma and membrane walls of pulmonary arterioles from PAH patients. Moreover,
plasma HSP90 levels positively correlated with mean pulmonary arterial pressure
and C-reactive protein. In a monocrotaline-induced rat model of PH, we found that
17-AAG, a HSP90-inhibitor, alleviated the progress of PH, demonstrated by lower
pulmonary arterial pressure and absence of right ventricular hypertrophy.
Immunohistochemical staining demonstrated that 17-AAG improved pulmonary
arteriole remodeling on the basis of reduced wall thickness and wall area. The
inflammatory response attributed to PH could be attenuated by 17-AAG through
reduction of NF-?B signaling. Moreover, 17-AAG was found to suppress
PDGF-stimulated proliferation and migration of pulmonary artery smooth muscle
cells (PASMCs) through induction of cell cycle arrest in the G1 phase. In
conclusion, HSP90 inhibitor 17-AAG could improve pulmonary arteriole remodeling
via inhibiting the excessive proliferation of PASMCs, and inhibition of HSP90 may
represent a therapeutic avenue for the treatment of PAH.