TGF-β mediates aortic smooth muscle cell senescence in Marfan syndrome

Formation of aortic aneurysms as a consequence of augmented transforming growth factor beta (TGF-beta) signaling and vascular smooth muscle cell (VSMC) dysfunction is a potentially lethal complication of Marfan syndrome (MFS). Here, we examined VSMC senescence in patients with MFS and explored the potential mechanisms that link VSMC senescence and TGF-beta. Tissue was harvested from the ascending aorta of control donors and MFS patients, and VSMCs were isolated. Senescence-associated beta-galactosidase (SA-beta-gal) activity and expression of senescence-related proteins (p53, p21) were significantly higher in aneurysmal tissue from MFS patients than in healthy aortic tissue from control donors. Compared to control-VSMCs, MFS-VSMCs were larger with higher levels of both SA-beta-gal activity and mitochondria! reactive oxygen species (ROS). In addition, TGF-beta 1 levels were much higher in MFS- than control-VSMCs. TGF-beta 1 induced VSMC senescence through excessive ROS generation. This effect was suppressed by Mito-tempo, a mitochondria-targeted antioxidant, or SC-514, a NF-kappa B inhibitor. This suggests TGF-beta 1 induces VSMC senescence through ROS-mediated activation of NF-kappa B signaling. It thus appears that a TGF-beta 1/ROS/NF-kappa B axis may mediate VSMC senescence and aneurysm formation in MFS patients. This finding could serve as the basis for a novel strategy for treating aortic aneurysm in MFS.