Elsevier

Ageing Research Reviews

Volume 7, Issue 2, April 2008, Pages 137-146
Ageing Research Reviews

Review
Cyclin-dependent kinase inhibitor p16INK4a and telomerase may co-modulate endothelial progenitor cells senescence

https://doi.org/10.1016/j.arr.2008.02.001Get rights and content

Abstract

Endothelial cells (ECs) damage is an initial and pivotal step in the formation of atherosclerosis. Endothelial progenitor cells (EPCs), which have been considered as the precursor of ECs, can migrate and home to the site of injured ECs to divide into mature ECs and keep the integrity of the endothelial monolayer. It has been shown that the number and function of EPCs are negatively correlated with various atherosclerotic risk factors. This finding may be explained partly by accelerated senescence of EPCs induced by telomere attrition or shortening owning to oxidative stress and accumulative ROS. However, elevated telomerase activity which extends the telomere cannot lead to cellular immortal in the presence of the cyclin-dependent kinase inhibitor p16INK4a. Researchers have the opinion that senescence is the balance between the regeneration and cancer. High expression of phosphorylated p16INK4a, which is caused by oxidative stress and accumulative ROS, can prevent tumor cells from unlimited division and becoming malignant ones by accelerating premalignant cells premature senescence. It has been demonstrated that the expression of p16INK4a increases remarkably with age due to oxidative stress and accumulative ROS in some stem and progenitor cells, and regulates these cells age-dependent senescence. It is observed that telomeres shortening exists in these cells. Therefore, it can be hypothesized that p16INK4a, together with telomerase, may co-modulate EPCs senescence.

Introduction

Although the exact molecular mechanisms of atherosclerosis are still incompletely understood, accumulating evidences have demonstrated that endothelial cells (ECs), which form an endothelial monolayer between circulating blood and the rest of the vascular wall, play an important role in this process (Ross, 1999). According to the response-to-injury hypothesis, ECs damage and dysfunction induced by various atherosclerotic risk factors such as hypertension, diabetes, hyperlipidemia, can initiate the process of atherosclerosis, trigger the concomitant macrophages and lipids deposition, and then lead to the progression of atherosclerosis (Perticone et al., 2001, O’Driscoll et al., 1997, John et al., 1998, Heitzer et al., 2001). Recent studies have shown that endothelial progenitor cells (EPCs) are precursors of vascular ECs, and have the ability to regenerate ECs, displace impaired ones and maintain the integrity of the endothelial monolayer (Walter et al., 2002, Griese et al., 2003, Dimmeler and Zeiher, 2004). However, it is evidenced that the number of circulating EPCs in atherosclerotic animal models and patients with coronary artery disease (CAD) is significantly reduced. Likewise, their migration, aggregation and division potentials are remarkably decreased. Meanwhile, with the accumulative atherosclerotic risk factors, the above trend shows dramatically (Vasa et al., 2001).

Telomeres are key structural elements for the protection and maintenance of linear chromosomes. Human cells in culture that divide in the absence of telomerase experience telomere shortening on the order of 50–100 bp per cell division (Harley et al., 1990). Critically shorten telomere ultimately triggers telomere decapping, and leads to cellular senescence (Titia de Lange, 2005).

The cyclin-dependent kinase inhibitor p16INK4a, which is a tumor suppressor has raised researchers great interests in tumor molecular exploration and therapy. As a protective mechanism, increased expression of p16INK4a caused by excessive cell division and oxidative stress can cause cell division arrest and block premalignant cells to further divide into malignant cell (Wu et al., 2004, Collado et al., 2005). Replicative senescence, namely cell division arrest, plays a critical role in this protective mechanism. In addition, recent studies have shown that p16INK4a is implicated in senescence of some kinds of stem cells and progenitor cells while the molecular mechanisms have not been explicitly determined (Molofsky et al., 2006, Krishnamurthy et al., 2006, Janzen et al., 2006). In this present review, the pro-senescent mechanisms of p16INK4a, and the possible roles of p16INK4a and telomerase in EPCs senescence will be discussed.

Section snippets

ECs regeneration and EPCs

As mentioned above, the integrity of endothelial monolayer is of crucial importance to protect vascular wall from atherosclerosis. Various atherosclerotic risk factors injury the natural endothelium barrier, then macrophages and lipids are penetrated through the damaged and dysfunctional ECs. Lipid oxidative, macrophage phagocytosis and the following foam cells formation happen under the endothelial monolayer, which initiates the process of atherosclerosis ultimately.

The repair and regeneration

Telomere, telomerase and EPCs senescence

As a consequence of semi-conservative DNA replication, the extreme termini of chromosomes are not duplicated completely, resulting in successive telomeres shortening with each cell division (Blasco, 2005). Telomerase, a ribonucleoprotein reverse transcriptase, can catalyze the addition of telomeric repeats (TTAGGG)n to telomeres and stabilize telomeres length (Bodnar et al., 1998, Wong and Collins, 2003). In the absence of telomerase, telomeres progressively shorten, ultimately leading to

The role of p16INK4a as a tumor suppressor

Previous studies have demonstrated that cyclin-dependent kinase (CDK) inhibitor p16INK4a acts as a tumor suppressor. p16INK4a is a member of the INK4 family including p15INK4b, p16INK4a, p18INK4c, and p19INK4d. Elevated expression of p16INK4a can bind and inhibit CDK4 and CDK6, then lead to the active, hypophosphorylated Rb; p16 can also disrupt the CDK complexes that release other sequestered CDK inhibitors such as p27 from these complexes to inhibit other CDK, especially CDK2, then increase

Conclusion

EPCs senescence plays an important role in ECs repair. Telomerase–telomere mechanism is one of various senescent mechanisms, and can influence EPCs senescence. Telomerase activity is regulated in a cell-dependent manner, and influenced by the level of oxidative stress. High expression of p16INK4a closely correlates with some kinds of stem and progenitor cells senescence, and is regarded as a senescent marker. The mechanisms by which p16INK4a leads to cellular senescence may be interpreted by

Acknowledgements

This manuscript has been supported by National Natural Science Foundation of China (Project 30500209) and Program for New Century Excellent Talents in University (Project NCET-06-0684).

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      Deficiency of the nucleotide excision repair pathway renders cells more sensitive to oxidative stress causing increased telomere attrition (Ting et al., 2010). Oxidative stress increases the expression of phosphorylated cyclin-dependent kinase inhibitor p16 (INK4a) and this induces senescence in endothelial progenitor cells (EPCs) associated with shortening of telomere length (Yang et al., 2008). Increased oxidative stress may enhance the expression of miR-195 that inhibits SIRT1 leading to senescence associated with shortening of telomeres (Kondo et al., 2016).

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