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

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 β-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.