Effects Of Heat Shock Protein 90 On The Progress Of Smooth Muscle Cell Phenotypic Switch In The Development Of Aortic Dissection

Background and objectiveHeat shock proteins are a class of highly conserved molecular chaperone families in the process of biological evolution.They are significantly up-regulated to enhance cell stress and adaptability when cells are stimulated by intracellular environment disorders and external stimulation.HSP90,an important member of the HSPs family,plays an important role in the growth of normal and abnormal cells.In recent years,with the research of HSP90 inhibitors,17-AAG is a representative of the Glanamycin derivative that have entered a number of hematological and solid tumor mono-drug therapy of stage II clinical trials.While,HSP 90 in the cardiovascular field of action mechanism is also gradually in-depth,several research had shown that HSP90 inhibitor 17-AAG can stable the atherosclerotic plaque in atherosclerosis.The relevant certain effects had been found in pulmonary hypertension and abdominal aneurysms,but its role in the development of aortic dissection has not been reported.Aortic dissection is one of the most critical emergency disotders,although the current diagnosis and treatment has been significantly improved,the mortality of acute aortic dissection remains high level.In recent years for the basic study development of aortic dissection,not only the degeneration of elastin but also the different biological characteristics of smooth muscle cells are important pathologies progress.Therefore,the study of smooth muscle cells is gradually becoming the focus of the development of aortic dissection.The aim of this study was to determine the expression level of HSP90 in the development of aortic dissection and to determine whether it was related to the phenotype transformation of vessel smooth muscle cells.Then,we further confirmed the effect of HSP90 inhibitor on the biological function of smooth muscle cells at the cellular level.Finally,an HSP90 inhibitor was used to observe the therapeutic effect on the disease in aortic dissection animal model.MethodsAll clinical aorta samples and serum from TAD patients(n=20)were collected from aortic replacement surgery at Department of Cardiovascular Surgery,Changhai Hospital.All normal serum were collected from donors(n=20)and aorta samples were collected from organ donors(n=8).The RNA expression levels were detected by real-time PCR,andthe protein expression levels were detected by western blot and immunohistochemistry.Aortic smooth muscle cells(SMCs)were isolated from rats aorta.The primary thoracic aortic smooth muscle cells were isolated from SD rats by collagenase digestion.The changes of biological traits of rat thoracic aortic smooth muscle cells were induced by PDGF-bb,and the HSP90 inhibitor 17-DMAG was used to intervene.The biological function of the cells is tested by real-time PCR,western blot,CCK-8,wound scratch assay and flow cytometry analysis.Then,the effect of HSP90 inhibitor(17-DMAG)on AD progress was evaluated on AD mice model induced by ?-aminopropionitrile fumarate and angiotensin II.The HSP90 inhibitor 17-DMAG intervention model was used to determine whether the HSP90 inhibitor could prevent the aortic dissection from decreasing the mortality.Protein expression levels were detected by western blot.And tissues detected by routine staining and VB staining.ResultsIn clinical samples,HSP90 expression was detected increased in aortic walls from TAD patients,and expressed in the smooth muscle cells of vascular wall,and significantly positive corrected with SMCs synthetic phenotypic marker.At the cellular level,17-DMAG suppressed phenotypic switch of SMCs induced by PDGF-bb,and significantly depressed the excessive proliferation and migration of SMCs.In mouse model of AD,treatment with17-DMAG effectively reduced the mortality.Histological examination confirmed that17-DMAG alleviated the loss of elastic fiber integrity and reduction of SMCs contraction.Conclusion17-DMAG could effectively alleviate the AD progress and reduce the mortality of AD model by suppressing SMCs phenotypic switch,and inhibition of HSP90 might be a potential avenue for AD therapy.