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Cardiovascular Research 2004 61(4):693-704; doi:10.1016/j.cardiores.2003.12.008
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

p21Waf1/Cip1/Sdi1 mediates shear stress-dependent antiapoptotic function

Stefania Mattiussia,b,1, Paolo Turrinia,1,2, Lucia Testolina, Fabio Martellia, Germana Zaccagninic, Antonella Mangonic, Laura M Barlucchia, Annalisa Antoninia, Barbara Illia, Corrado Ciriellia, Julio Padrona,1, Chiara Nicolòb, Roberto Testib, Francesco Osculatid, Paolo Bigliolic, Maurizio C Capogrossia and Carlo Gaetano*,a

aLaboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta, 104, 00167 Rome, Italy
bUniversità degli Studi di Roma "Tor Vergata", Italy
cIstituto Cardiologico Fondazione "I. Monzino", IRCCS, Milan, Italy
dDipartimento di Scienze Biomediche e Morfologiche, Sezione di Istologia ed Anatomia, Facoltà di Medicina e Chirurgia, Università di Verona, Verona, Italy

* Corresponding author. Tel.: +39-6-66464794; fax: +39-6-66462430. gaetano{at}idi.it

1 Current address: Istituto Ricerche di Biologia Molecolare (IRBM) "P. Angeletti", Pomezia, Roma, Italy.

Objective: The antiapoptotic effect of p21Waf1/Cip1/Sdi1 (p21) was examined in human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress (SS) or to the nitric oxide donor sodium nitroprusside (SNP) and in a mouse model of hindlimb ischemia. Methods: In vitro: Cells were cultured without serum and in the presence of cobalt chloride to simulate hypoxia for 12 h (T0). Shear stress was applied to endothelial cells for additional 12 h. In vivo: Hindlimb ischemia was realized in mice by femoral artery ligation. SNP was acutely administered by subcutaneous injection or by Alzet osmotic pumps for a longer treatment. Results: At T0, HUVEC were either exposed to SS (15 dyn/cm2/s–1), treated with SNP or kept in static condition (ST) for 1–12 h; after additional 12 h in ST, 30–35% of cells still alive at T0 had died. In this condition, both SS and SNP treatments markedly increased p21 levels and reduced apoptosis in HUVEC. Recombinant adenoviruses carrying p21 (AdCMV.p21) or antisense p21 (AdCMV.ASp21) cDNA revealed that AdCMV.p21-infected HUVEC were protected from death while AdCMV.ASp21 reduced SS- and SNP-dependent protection from apoptosis. In mice, apoptosis was detected in endothelial cells of ischemic hindlimbs as early as 8 h after femoral artery ligation. Treatment with SNP enhanced p21 expression and protected ischemic tissue from damage. Remarkably, direct in vivo injection of AdCMV.p21 significantly reduced the number of apoptotic nuclei in the presence of ischemia. Conclusions: The present study establishes that, under our experimental conditions, (a) p21 plays an important role in SS and nitric oxide antiapoptotic effect in vitro, and (b) p21 gene transfer prevents apoptosis in vitro and in vivo, following acute interruption of blood flow.

KEYWORDS Shear stress; p21; Apoptosis; Flow; Hypoxia; Ischemia

1 Equal contributors.

Time for primary review 16 days


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