Abstract 11869: ACDF-1Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A11869-A11869
• Main Authors: Hu, Lina, Ishii, Hideki, Wu, Hongxian, Suzuki, Susumu, Inoue, Aiko, Shi, Guo-Ping, Murohara, Toyoaki, Kuzuya, Masafumi, Cheng, Xian Wu
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

BackgroundAlthough apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis after injury, the communication between these two cellular events has not been evaluated. Here we report an inextricable communicative link between apoptosis and smooth muscle cell (SMC) proliferation in the promotion of vascular remodeling after injury.Methods and ResultsCathepsin K (CatK)-mediated caspase-8 maturation is a key initial step for oxidative stress-induced SMC apoptosis. Apoptotic cells generate a potential growth-stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that CatK regulates is apoptotic cell-derived factor-1 (called ACDF-1), which can potently stimulate the growth of surviving neighboring SMCs via the activation of PI3K/Akt/p38MAPK-depended and -independent mTOR signaling cascades. We observed that CatK deficiency substantially mitigated neointimal hyperplasia via the reduction of toll-like receptor-2/caspase-8-medciated ACDF-1 expression. Interestingly, ACDF-1 blocking with its neutralizing antibody suppressed neointima formation and remodeling in response to injury in wild-type mice. Oppositely, administration of recombinant mouse ACDF-1 accelerated injury-induced vascular actions.ConclusionsThis is the first study detailing ACDF-1 as a communicator between apoptosis and proliferation during injury-related vascular remodeling and neointimal hyperplasia. These data suggested that ACDF-1 is thus a novel target for the treatment of apoptosis-based hyperproliferative disorders.