Progranulin expression in advanced human atherosclerotic plaque.
BACKGROUND
Progranulin (PGRN) is a unique growth factor that plays an important role in cutaneous wound healing. It has an anti-inflammatory effect and promotes cell proliferation. However, when it is degraded to granulin peptides (GRNs) by neutrophil proteases, a pro-inflammatory reaction occurs. Since injury, inflammation and repair are common features in the progression of atherosclerosis, it is conceivable that PGRN plays a role in atherogenesis.


RESULTS
Immunohistochemical analysis of human carotid endoatherectomy specimens indicated that vascular smooth muscle cells (vSMCs) in the intima expressed PGRN. Some macrophages in the plaque also expressed PGRN. We assessed the effect of PGRN on a human monocytic leukemia cell line (THP-1) and human aortic smooth muscle cells (HASMCs). PGRN alone had no effect on HASMC or THP-1 proliferation or migration. However, when THP-1 cells were stimulated with MCP-1, the number of migrated cells decreased in a PGRN-dose-dependent manner. TNF-alpha-induced HASMC migration was enhanced only at 10nM of PGRN. Interleukin-8 (IL-8) secretion from HASMCs was reduced by forced expression of PGRN and increased by RNAi-mediated knockdown of PGRN. While exogenous treatment with recombinant PGRN decreased IL-8 secretion, degraded recombinant GRNs increased IL-8 secretion from HASMCs.


CONCLUSIONS
The expression of PGRN mainly reduces inflammation and its degradation into GRNs enhances inflammation in atherosclerotic plaque and may contribute to the progression of atherosclerosis.
Kojima
Yoji
Y
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Ono
Koh
K
Inoue
Katsumi
K
Takagi
Yasushi
Y
Kikuta
Ken-ichiro
K
Nishimura
Masaki
M
Yoshida
Yoshinori
Y
Nakashima
Yasuhiro
Y
Matsumae
Hironobu
H
Furukawa
Yutaka
Y
Mikuni
Nobuhiro
N
Nobuyoshi
Masakiyo
M
Kimura
Takeshi
T
Kita
Toru
T
Tanaka
Makoto
M