Functional characterization of a putative serine carboxypeptidase in vascular smooth muscle cells.
BACKGROUND
We previously identified a novel serine carboxypeptidase, SCPEP1, that undergoes cleavage across all tissues where it is expressed. SCPEP1 bears the signature catalytic triad found in all serine carboxypeptidases, but its biological function is completely unknown.


OBJECTIVE
To begin elucidating the functions of SCPEP1 in vitro and in the vessel wall after injury.


RESULTS
Cultured smooth muscle cells were transduced with adenovirus carrying wild-type Scpep1, a short hairpin RNA to Scpep1, or variants of Scpep1 with mutations that disrupt the catalytic triad domain or SCPEP1 cleavage. Western blotting of key growth regulators or growth and migratory responses were assessed following SCPEP1 gain- or loss-of-function in smooth muscle cells. Vascular injury-induced remodeling and cell proliferation were evaluated in wild-type or newly created Scpep1 knockout mice. Overexpression of wild-type or cleavage-defective SCPEP1, but not a catalytic triad mutant SCPEP1, promotes smooth muscle cell proliferation and migration in vitro. A short hairpin RNA to Scpep1 blunts endogenous growth, which is rescued on concurrent expression of Scpep1 carrying silent mutations that evade knockdown. SCPEP1 protein is highly expressed in the neointima of 2 models of vascular remodeling. Scpep1-null mice show decreases in medial and intimal cell proliferation as well as vessel remodeling following arterial injury.


CONCLUSIONS
SCPEP1 promotes smooth muscle cell proliferation and migration in a catalytic triad-dependent, cleavage-independent manner. SCPEP1 represents a new mediator of vascular remodeling and a potential therapeutic target for the treatment of vascular occlusive diseases.
Lee
Ting-Hein
TH
Aab Cardiovascular Research Institute, Box CVRI, University of Rochester School of Medicine & Dentistry, 211 Bailey Rd, Rochester, New York 14586, USA.
Chen
Jiyuan
J
Miano
Joseph M
JM
D000256:Adenoviridae; D000818:Animals; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D014161:Transduction, Genetic; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D017540:Tunica Media / Q000166:cytology / Q000378:metabolism
D002268:Carboxypeptidases; C486671:Scpep1 protein, mouse