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HSP90 inhibitor 17-DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch.

ABSTRACT: Thoracic aortic dissection (TAD) is a highly lethal vascular disease characterized by medial degeneration. Heat shock protein 90 (HSP90) had been proved as a potential target for a variety of diseases. The aim of this study was to identify the effect of HSP90 inhibitor on TAD progress, and to explore the potential utility of HSP90 inhibitors as therapeutic avenue for TAD. In clinical samples, the elevated HSP90 expression was detected in aortic walls from TAD patients (n=20) by real-time PCR and western blot, and was positively correlated with osteopontin (OPN), a synthetic phenotypic marker of smooth muscle cells (SMCs), while negatively correlated with SM22, a contractile phenotypic marker. In a ?-aminopropionitrile fumarate-induced AD mice model, 17-DMAG, a HSP90-inhibitor, effectively reduced the incidence and mortality of TAD. Histological examination confirmed that 17-DMAG significantly alleviated the loss of elastic fibers integrity. Meanwhile, the phenotypic switch of SMCs was significantly suppressed by 17-DMAG, demonstrated by the change of phenotypic markers expression. On the cellular level, 17-DMAG suppressed phenotypic switch of SMCs induced by PDGF-bb, and significantly depressed the excessive proliferation and migration of SMCs. Flow cytometry analysis showed that 17-DMAG induced cell cycle arrest in G1 phase. In summary, 17-DMAG could effectively alleviate the TAD progress by suppressing SMCs phenotypic switch, and inhibition of HSP90 might be a potential avenue for TAD therapy.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC6357309 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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HSP90 inhibitor 17-DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch.

Zhao Zhimin Z Wang Yang Y Li Songhua S Liu Suxuan S Liu Yang Y Yu Yongchao Y Yang Fan F Xu Zhiyun Z Wang Guokun G

American journal of translational research 20190115 1

Thoracic aortic dissection (TAD) is a highly lethal vascular disease characterized by medial degeneration. Heat shock protein 90 (HSP90) had been proved as a potential target for a variety of diseases. The aim of this study was to identify the effect of HSP90 inhibitor on TAD progress, and to explore the potential utility of HSP90 inhibitors as therapeutic avenue for TAD. In clinical samples, the elevated HSP90 expression was detected in aortic walls from TAD patients (n=20) by real-time PCR and ...[more]

PMID: 30788006

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Project description:PurposeTo identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis.MethodsA total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC(0-24 h), using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose.ResultsA 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC(0-24 h) for the median dose of 36 mg/m(2) was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC(0-24 h) considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h.ConclusionsPopulation pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.

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HSP90 inhibitor 17-DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch.

Publications

HSP90 inhibitor 17-DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch.

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