Matrix metalloproteinase 2 activation of transforming growth factor-β1 (TGF-β1) and TGF-β1-type II receptor signaling within the aged arterial wall

被引：210

作者：

Wang, Mingyi ^{[1
]}

Zhao, Di ^{[1
]}

Spinetti, Gaia ^{[1
]}

Zhang, Jing ^{[1
]}

Jiang, Li-Qun ^{[1
]}

Pintus, Gianfranco ^{[1
]}

Monticone, Robert ^{[1
]}

Lakatta, Edward G. ^{[1
]}

机构：

[1] NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2006年 / 26卷 / 07期

关键词：

aging; metalloproteinases; TGF-beta; 1; signaling; arterial remodeling;

D O I：

10.1161/01.ATV.0000225777.58488.f2

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective - To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-beta 1 (TGF-beta 1) activation status and downstream signaling during arterial aging. Methods and Results - Western blotting and immunostaining showed that latent and activated TGF-beta 1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-beta 1-type II receptor (T beta RII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-beta 1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-beta 1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-beta 1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2. Conclusions - Active TGF-beta 1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging. TGF-beta 1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2 - activated TGF-beta 1, and subsequently T beta RII signaling, is a novel molecular mechanism for arterial aging.

引用

页码：1503 / 1509

页数：7

共 26 条

[1]

[Anonymous], ARTERIAL STIFFNESS H

[2] Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation [J].

Baramova, EN ;

Bajou, K ;

Remacle, A ;

LHoir, C ;

Krell, HW ;

Weidle, UH ;

Noel, A ;

Foidart, JM .

FEBS LETTERS, 1997, 405 (02) :157-162

[3] Latent TGF-β binding protein-3 (LTBP-3) requires binding to TGF-β for secretion [J].

Chen, Y ;

Dabovic, B ;

Annes, JP ;

Rifkin, DB .

FEBS LETTERS, 2002, 517 (1-3) :277-280

[4] Release of biologically active TGF-β from airway smooth muscle cells induces autocrine synthesis of collagen [J].

Coutts, A ;

Chen, G ;

Stephens, N ;

Hirst, S ;

Douglas, D ;

Eichholtz, T ;

Khalil, N .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2001, 280 (05) :L999-L1008

[5] THE INFLUENCE OF AGING ON ANGIOTENSINOGEN PRODUCTION BY RAT VASCULAR SMOOTH-MUSCLE CELLS-INVITRO [J].

EGGENA, P ;

MORIN, AM ;

BARRETT, JD ;

KRALL, JF .

CLINICAL AND EXPERIMENTAL HYPERTENSION PART A-THEORY AND PRACTICE, 1988, 10 (04) :597-603

[6] Transforming growth factor-β is activated by plasmin and inhibits smooth muscle cell death in human saphenous vein [J].

George, SJ ;

Johnson, JL ;

Smith, MA ;

Angelini, GD ;

Jackson, CL .

JOURNAL OF VASCULAR RESEARCH, 2005, 42 (03) :247-254

[7] Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins [J].

George, SJ ;

Baker, AH ;

Angelini, GD ;

Newby, AC .

GENE THERAPY, 1998, 5 (11) :1552-1560

[8] Analysis of tissue inhibitor of metalloproteinases-2 effect on pro-matrix metalloproteinase-2 activation by membrane-type 1 matrix metalloproteinase using baculovirus/insect-cell expression system [J].

Jo, Y ;

Yeon, J ;

Kim, HJ ;

Lee, ST .

BIOCHEMICAL JOURNAL, 2000, 345 :511-519

[9] Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis [J].

Karsdal, MA ;

Larsen, L ;

Engsig, MT ;

Lou, H ;

Ferreras, M ;

Lochter, A ;

Delaissé, JM ;

Foged, NT .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (46) :44061-44067

[10] Improved arterial compliance by a novel advanced glycation end-product crosslink breaker [J].

Kass, DA ;

Shapiro, EP ;

Kawaguchi, M ;

Capriotti, AR ;

Scuteri, A ;

deGroof, RC ;

Lakatta, EG .

CIRCULATION, 2001, 104 (13) :1464-1470

← 1 2 3 →