TY - JOUR
T1 - Plf-1 (Proliferin-1) modulates smooth muscle cell proliferation and development of experimental intimal hyperplasia
AU - Hu, Lina
AU - Huang, Zhe
AU - Ishii, Hideki
AU - Wu, Hongxian
AU - Suzuki, Susumu
AU - Inoue, Aiko
AU - Kim, Weon
AU - Jiang, Haiying
AU - Li, Xiang
AU - Zhu, Enbo
AU - Piao, Limei
AU - Zhao, Guangxian
AU - Lei, Yanna
AU - Okumura, Kenji
AU - Shi, Guo Ping
AU - Murohara, Toyoaki
AU - Kuzuya, Masafumi
AU - Cheng, Xian Wu
N1 - Funding Information:
This work was supported, in part, by the National Natural Science Foundation of China (NSFC, CHINA) (Nos. 81260068, 81560240, 81660240, 81770485, 81760091, and AD19120092) and by grants from the Japan Society for the Promotion of Science (JSPS, JAPAN) (Nos. 15H04801, 15H04802). In addition, Hu is a postdoctoral fellow of the Japan Society Science (JSPS, JAPAN) (No. 26-04418).
Funding Information:
This work was supported, in part, by the National Natural Science Foundation of China (NSFC, CHINA) (Nos. 81260068, 81560240, 81660240, 81770485, 81760091, and AD19120092) and by grants from the Japan Society for the Promotion of Science (JSPS, JAPAN) (Nos. 15H04801, 15H04802). In addition, Hu is a postdoctoral fellow of the Japan Society for the Promotion of Science (JSPS, JAPAN) (No. 26-04418).
Publisher Copyright:
© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2019
Y1 - 2019
N2 - Background-—Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results-—Cathepsin K–mediated caspase-8 maturation is a key initial step for oxidative stress–induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth-stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF-1 (proliferin-1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3-kinase/protein kinase B/p38 mitogen-activated protein kinase)-dependent and-independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll-like receptor-2/caspase-8–mediated PLF-1 expression. Interestingly, PLF-1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild-type mice. Contrarily, administration of recombinant mouse PLF-1 accelerated injury-induced vascular actions. Conclusions-—This is the first study detailing PLF-1 as a communicator between apoptosis and proliferation during injury-related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis-driven expression of PLF-1 is thus a novel target for treatment of apoptosis-based hyperproliferative disorders.
AB - Background-—Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results-—Cathepsin K–mediated caspase-8 maturation is a key initial step for oxidative stress–induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth-stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF-1 (proliferin-1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3-kinase/protein kinase B/p38 mitogen-activated protein kinase)-dependent and-independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll-like receptor-2/caspase-8–mediated PLF-1 expression. Interestingly, PLF-1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild-type mice. Contrarily, administration of recombinant mouse PLF-1 accelerated injury-induced vascular actions. Conclusions-—This is the first study detailing PLF-1 as a communicator between apoptosis and proliferation during injury-related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis-driven expression of PLF-1 is thus a novel target for treatment of apoptosis-based hyperproliferative disorders.
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U2 - 10.1161/JAHA.117.005886
DO - 10.1161/JAHA.117.005886
M3 - Article
C2 - 31838975
AN - SCOPUS:85076559517
VL - 8
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 24
M1 - e005886
ER -