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Cardiovascular Research 2004 61(4):648-650; doi:10.1016/j.cardiores.2004.01.003
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

P21Waf1/Cip1 in endothelial cell survival

Fawzi Aoudjit and Jean Sévigny*

Centre de recherche en Rhumatologie et Immunologie, Centre hospitalier de l’Université Laval, 2705 Boulevard Laurier, Room T1-49, Ste.-Foy, Québec, Canada G1V 4G2

* Corresponding author. Tel.: +1-418-656-4141x46319; fax: +1-418-654-2765. jean.sevigny{at}crchul.ulaval.ca

Received 22 December 2003; See article by Mattiussi et al. [13] (pages 693–704) in this issue.

The role of endothelial cells in pathological processes is the focus of intensive research. In this context, programmed cell death (apoptosis) plays an important function. Although apoptosis can be seen in many instances as detrimental in the cardiovascular system, it also has beneficial functions. For example, the occurrence of endothelial cell apoptosis has deleterious effects on the development of the cardiovascular system that lead to embryonal lethality. An increase of apoptosis in endothelial cells also contributes to various pathological conditions such as atherosclerosis, tissue destruction during vascular injury, inflammation and allograft arteriopathy, and cellular resistance to apoptosis is necessary for the maintenance of blood vessel integrity and for angiogenesis [1]. However, in the adult, endothelial cell apoptosis is required to prevent neovascularization [2]. Therefore, the tight regulation of endothelial cell apoptosis and function is of prime importance.

The homeostasis and function of endothelial cells are controlled by several chemical signals such as VEGF, vitronectin, nucleotides, oxidized LDL, and their membrane receptors [2]. In addition, growing evidence indicates that mechanical signals are also important in endothelial cell functions as they influence cell shape and structure, growth, and other characteristics. The mechanical signals to which cells are exposed in vivo include gravitational force, mechanical stress and shear stress. Endothelial cells are particularly exposed to the latter force associated with blood flow. They adapt to sustained shear stress, which is believed to shape the vascular bed through remodelling in order to maintain optimal circulation [3]. Mechanical signals generated by shear stress are mediated by several signalling molecules that include ion channels, membrane receptors (possibly located in specialized microdomains such as caveolae), G proteins, integrins, and intercellular junction proteins [4–6]. These so-called mechanosensors transduce a variety of signals that result in the generation of reactive oxygen species, nitric oxide, and activation of gene expression.

Depending upon intensity and fluctuations, shear stress initiates different, or even opposing, (patho)physiological actions on endothelial cells. For example, while an increase in shear stress is associated with hypertension, a decrease contributes to thrombotic occlusion [7]. Depending on the fine variations, shear stress can be atheroprotective or favour atherosclerosis. The cytoprotective effects of laminar shear stress in atherosclerosis are associated with several mechanisms including inhibition of thrombosis, inhibition of endothelial cell permeability, and inhibition of endothelial apoptosis [8,9]. In agreement with these observations, atherosclerosis associated with endothelial cell apoptosis occurs in areas of low fluid shear stress. Several studies have reported that shear stress protects endothelial cells from apoptosis triggered by serum deprivation, TNF{alpha}, and oxidative stress [2,10,11].

Given the importance of shear stress in endothelial cell apoptosis, the investigation of the molecular mechanisms by which endothelial cells sense and transduce shear stress signals to modulate death and survival may lead to the identification of new therapeutic targets. In that regard, several studies have shown that the anti-apoptotic effects of shear stress on endothelial cells are mediated through numerous signalling molecules that include the activation of the serine/threonine kinase Akt, the release of NO, the activation of Ras/MAPK [4,5], and NF-{kappa}B signalling [12]. In this issue of Cardiovascular Research, Mattiussi et al. [13] present a new piece of information about the cytoprotective mechanisms of shear stress in endothelial cell function. They show in an in vitro system that shear stress and NO induced the expression of the CDK inhibitor p21Waf1/Cip1 (p21) in endothelial cells and that the latter mediated protection to these cells from serum starvation-induced apoptosis. They also confirmed these data in experiments involving murine hindlimb ischemia.

P21 is the founding member of the Cip/Kip family of cyclin-dependent kinase inhibitors that also includes p27 and p57 [14]. These molecules bind to cyclin/CDK complexes and inhibit their activity, which is essential for cell cycle progression. P21 preferentially binds to cyclin/CDK2 complexes that are necessary for the transition from the G1 to the S phase. In addition to its role in growth arrest, p21 also has an anti-apoptotic function in several cellular models [14].

Mattiussi et al. have shown that when human umbilical vein endothelial cells were starved for 12 h and then kept either under static culture, exposed to laminar shear stress, or treated with the NO donor sodium nitroprusside (SNP) for an additional 1–12 h, only the cells exposed to shear stress or treated with SNP survived. These protective effects correlated with a time-dependent increase in the expression of p21. The authors also demonstrated that p21 overexpression alone could rescue endothelial cells from apoptosis and that the anti-apoptotic effect of shear stress and SNP was at least partly dependant on p21 expression. Finally, the authors tested the relevance of their findings in an animal model mimicking their in vitro studies (absence of shear stress, low O2, and serum deprivation). Using a model of hindlimb ischemia in mice, Mattiussi et al. confirmed that an increase in p21 expression protected the tissue from apoptosis and prevented the reduction in capillary density.

The work of Mattiussi et al. further extends previous studies on p21 by shedding light on its role in promoting the cytoprotective effects of shear stress and NO in endothelial cells. The evidence provided by this study also points to the role of p21 in physiological conditions. In another study, shear stress was shown to increase p21 protein levels that dephosphorylated the retinoblastoma protein and inhibited endothelial cell proliferation [15]. Maejima et al. [16] recently reported that the production of NO by cardiomyocytes during reperfusion upregulated p21 and protected the cells from apoptosis. Together, these studies indicate that p21 may be central for the cytoprotective effects of shear stress in endothelial cells and more generally to the protection of the cardiovascular system during ischemia.

The mechanisms involved in shear stress and NO-induced p21 expression in endothelial cells and the mechanism by which p21 inhibits endothelial cell apoptosis would certainly be an interesting focus of future research. Shear stress has been shown to induce an integrin-dependent activation of the PI 3-kinase/Akt pathway, which modulates NO production and inhibits caspase-3 activation [17–19]. Whether this pathway is involved in the induction of p21 expression under shear stress is an attractive possibility and warrants further investigation. Mattiussi et al. [13] have also shown that caspase-3 activation was inhibited by shear stress in their system. This could be the mechanism by which p21 promotes endothelial cell survival as it has previously been reported to directly inhibit the cleavage and activation of procaspase-3 [20]. It would also be of interest to determine whether the protective effect of p21 is specific to apoptosis induced by serum starvation or if it can be translated to other apoptotic inducers and to the Fas death pathway to which endothelial cells are sensitive under certain circumstances [21,22].


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