Tollip Negatively Regulates Vascular Smooth Muscle Cell-Mediated Neointima Formation by Suppressing Akt-Dependent Signaling.
BACKGROUND
Tollip, a well-established endogenous modulator of Toll-like receptor signaling, is involved in cardiovascular diseases. The aim of this study was to investigate the role of Tollip in neointima formation and its associated mechanisms.


METHODS AND RESULTS
In this study, transient increases in Tollip expression were observed in platelet-derived growth factor-BB-treated vascular smooth muscle cells and following vascular injury in mice. We then applied loss-of-function and gain-of-function approaches to elucidate the effects of Tollip on neointima formation. While exaggerated neointima formation was observed in Tollip-deficient murine neointima formation models, Tollip overexpression alleviated vascular injury-induced neointima formation by preventing vascular smooth muscle cell proliferation, dedifferentiation, and migration. Mechanistically, we demonstrated that Tollip overexpression may exert a protective role in the vasculature by suppressing Akt-dependent signaling, which was further confirmed in rescue experiments using the Akt-specific inhibitor (AKTI).


CONCLUSIONS
Our findings indicate that Tollip protects against neointima formation by negatively regulating vascular smooth muscle cell proliferation, dedifferentiation, and migration in an Akt-dependent manner. Upregulation of Tollip may be a promising strategy for treating vascular remodeling-related diseases.
['Zhi|Hong|H|', 'Gong|Fu-Han|FH|', 'Cheng|Wen-Lin|WL|', 'Zhu|Kongbo|K|', 'Chen|Long|L|', 'Yao|Yuyu|Y|', 'Ye|Xingzhou|X|', 'Zhu|Xue-Yong|XY|', 'Li|Hongliang|H|']
D000818:Animals D020212:Carotid Artery Injuries D002342:Carotid Artery, External D054337:Cell Dedifferentiation D002465:Cell Movement D049109:Cell Proliferation D002478:Cells, Cultured D004195:Disease Models, Animal D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D058426:Neointima D058729:Peripheral Arterial Disease D051057:Proto-Oncogene Proteins c-akt D015398:Signal Transduction
Tollip vascular smooth muscle neointima formation proliferation migration differentiation