Enhanced neointimal hyperplasia and carotid artery remodelling in sequestosome 1 deficient mice.
Deficiency in the signal adaptor protein sequestosome 1 (SQSTM1/A170/p62) in mice is associated with mature-onset obesity, accompanied by insulin and leptin resistance. We previously established that redox sensitive transcription factor Nrf2 up-regulates SQSTM1 expression in response to atherogenic stimuli or laminar shear stress in vascular cells, and here examine the role of SQSTM1 in neointimal hyperplasia and vascular remodelling in vivo following carotid artery ligation. Neointimal hyperplasia was markedly enhanced at ligation sites after 3 weeks in SQSTM1(-/-) compared with wild-type (WT) mice. The intimal area and stenotic ratio were, respectively, 2.1- and 1.7-fold higher in SQSTM1(-/-) mice, indicating enhanced proliferation of vascular smooth muscle cells (SMCs). When aortic SMCs were isolated from WT and SQSTM1(-/-) mice and cultured in vitro, we found that SQSTM1(-/-) SMCs proliferated more rapidly in response to foetal calf serum (FCS) and attained 2-3-fold higher cell densities compared to WT SMCs. Moreover, migration of SQSTM1(-/-) SMCs was enhanced compared to WT SMCs. Early and late phases of p38(MAPK) activation in response to FCS stimulation were also more enhanced in SQSTM1(-/-) SMCs, and inhibitors of p38 and ERK1/2 signalling pathways significantly attenuated SMC proliferation. In summary, SQSTM1(-/-) mice exhibit enhanced neointimal hyperplasia and vascular remodelling following arterial ligation in vivo. The enhanced proliferation of SQSTM1(-/-) aortic SMCs in vitro highlights a novel role for SQSTM1 in suppressing smooth muscle proliferation following vascular injury.
Majors of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Rika
R
Sugimoto
Eiji
E
Warabi
Satoru
S
Katayanagi
Satoshi
S
Sakai
Junya
J
Uwayama
Toru
T
Yanagawa
Ayaka
A
Watanabe
Harumi
H
Harada
Kiyoshi
K
Kitamura
Noriko
N
Noguchi
Hiroshi
H
Yoshida
Richard C M
RC
Siow
Giovanni E
GE
Mann
Tetsuro
T
Ishii
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000172:deficiency* / Q000378:metabolism; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000071456:Sequestosome-1 Protein; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases