Download Atherosclerosis and Cell Cycle: Put the Brakes On!

Journal of the American College of Cardiology
© 2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Atherosclerosis and Cell Cycle:
Put the Brakes On!
Critical Role for
Cyclin-Dependent Kinase Inhibitors*
Rainer Wessely, MD, PHD
Duisburg, Germany
Regulation of cellular proliferation constitutes one of the
fundamental mechanisms of biology. In the context of
cardiovascular disease, imbalances in the delicate equilibrium between cell proliferation and programmed cell death
play a role in diseases such as in-stent restenosis (1), left
ventricular remodeling (2), cardiac allograft vasculopathy
(3), and, importantly, atherosclerosis (4).
See page 2258
Cell-cycle regulation is complex and involves numerous
endogenous factors that can positively or negatively interfere
with cell-cycle progression. Cell-cycle progression is governed by the temporarily coordinated synthesis, activation,
inhibition, and degradation of distinct families of regulatory
proteins (5). Cyclins and cyclin-dependent kinases (CDKs)
form stable complexes in their active states and function as
positive regulators of the cell cycle. The phase-specific
activation of distinct cyclin/CDK complexes regulates progression through the cell cycle. Cyclin/CDK activities are
associated with cyclin levels as well as CDK phosphorylation status. Different members of the CDK family, in
association with different cyclins, turn key switches
throughout the cell cycle; other family members regulate
transcription, differentiation, nutrient uptake, and other
functions. Cyclin-dependent kinase inhibitors (CKIs) are
negative regulators of the cell cycle (6).
CKIs are comprised of 2 major families: the CIP/KIP
family includes p21CIP1, p27KIP1, and p57KIP2, whereas the
INK4 family includes p15INK4B, p16INK4A, p18INK4C, and
p19INK4D. p27KIP1 is a major therapeutic target to prevent
restenosis by means of drug-eluting stents since, for example, sirolimus, the drug released from the Cypher stent
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Department of Cardiology and Angiology, Evangelisches BethesdaJohanniter-Klinikum, Duisburg, Germany.
Vol. 55, No. 20, 2010
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2010.02.017
platform (Cordis, Bridgewater, New Jersey), inhibits the
mammalian target of rapamycin (mTOR) that initiates a
pathway that leads to p27KIP1 degradation upon mitogenic
activation (7). Therefore, sirolimus interacts positively with
post-transcriptional levels of p27KIP1 and thus induces early
cell-cycle arrest in the G1 phase, which resembles the major
effect for inhibition of smooth muscle cell proliferation and
restenosis.
In this issue of the Journal, González-Navarro et al. (8)
unravel an as yet undefined role of p19ARF in mice deficient
in this particular gene and additionally lacking apolipoprotein E (apoE), an established mouse model of atherosclerosis. Besides p16INK4A, the CDKN2A gene locus on
chromosome 9 encodes a second open reading frame (ARF:
alternative reading frame) that encodes for a 14-kDa protein
in humans (p14ARF) or a 19-kDa protein in mice (p19ARF)
(Fig. 1A). In meticulously performed experiments, the
authors are able to establish a protective role for p19ARF in
the pathogenesis of atherosclerosis. This is mainly mediated
by a pro-apoptotic effect of p19ARF on macrophages and
vascular smooth muscle cells within atherosclerotic lesions.
Therefore, p19ARF deficiency leads to augmentation of
atherosclerosis independent of lipoprotein levels or proliferative plaque activity. The latter is an unexpected finding
since p19ARF functions as a negative regulator of proliferation. However, the authors found that p16INK4A can compensate for missing p19ARF activity, notably demonstrating
a redundancy of biological function for these proteins
encoded by the CDKN2A gene. A further important finding
of the study is that the pro-atherosclerotic phenotype could
exclusively be observed in regions highly prone to atherosclerotic lesion development, suggesting, as the authors
point out correctly, that p19ARF is less involved in the
initiation than in the progression of lesion development.
The findings of González-Navarro et al. (8) add further to
the scientific mosaic of the complex pathogenesis of atherosclerosis, which is a complicated interplay between genetics,
inflammation, apoptosis, proliferation, and senescence. It appears that CKIs are regulators of and important linkers
between these pathophysiological key processes. This is underscored by numerous observations that loss of tumor suppressor
proteins, such as members of the CIP/KIP family including
p27KIP (9) as well as p53 (10) or retinoblastoma protein (11) in
gene-targeted animal models, are associated with acceleration
of atherosclerotic lesion formation.
Recently, several genome-wide association studies revealed that the chromosome locus 9p21.3 is associated with
atherosclerosis (12,13). This locus, which is in close proximity to the genes CDKN2A (encoding for p16INK4A and
p19ARF in mice or p14ARF in man) and CDKN2B (encoding
for p15INK4B), spans 58 kb and encompasses multiple single
nucleotide polymorphisms (SNPs) in tight linkage disequilibrium. The biological functions of the CDKN2A gene
products are depicted in Figure 1A. Approximately 25% of
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Figure 1
Wessely
Atherosclerosis and Cell Cycle
Role of the CDKN2A Gene and CKIs
in Key Pathophysiological Processes
Associated With Atherosclerotic Lesion Formation
(A) Schematic depiction of the interaction of the gene products of the CDKN2A
gene, p19ARF (in man: p14ARF), and p16INK4A with various molecules associated with cell-cycle regulation and apoptosis. The cyclin-dependent kinase
inhibitor (CKI) p16INK4A induces cell-cycle arrest via inhibition of CDK-4 and -6
that associate with D-type cyclins to subsequently phosphorylate Rb, thereby
facilitating the dissociation of E2F that ultimately leads to entry into the cell
cycle. p19ARF inhibits MDM2, an important negative regulator of the tumor suppressor p53 that can induce the CKI p21CIP1, which subsequently inhibits
important G1/S CDKs such as CDK-2, -4, and -6. p53 is also a potent inducer
of apoptosis. MDM2 functions both as an E3 ubiquitin ligase as well as an inhibitor of p53 transcriptional activation. (B) Illustration of the complex interaction of
CDK inhibitors with major pathophysiological mechanisms of atherosclerosis.
CDK ⫽ cyclin-dependent kinase; Rb ⫽ retinoblastoma protein; Ub ⫽ ubiquitin.
Caucasians carry 2 copies of the risk allele and have an
approximately 1.5-fold increased risk for coronary artery disease (13). The increased risk is independent of typical atherosclerotic risk factors such as plasma lipids, hypertension, diabetes, obesity, and markers of inflammation. The findings
presented in the current study by González-Navarro et al. (8)
add to the emerging evidence of a pathophysiological link of
genomic susceptibility to an atherosclerotic phenotype.
JACC Vol. 55, No. 20, 2010
May 18, 2010:2269–71
Atherosclerosis is considered to be initiated by inflammatory mechanisms (14). However, in early as well as in
advanced lesions, vascular proliferation does play a pivotal
role in disease progression (4). CKIs can systemically and
locally inhibit both inflammatory (15) as well as proliferative
processes (16), predominantly by cell-cycle inhibition
and/or the induction of apoptosis in various cell types such
as macrophages or vascular smooth muscle cells. Therefore,
novel therapeutic concepts might take advantage of these
pleiotropic CKI effects. In this context, it is interesting to
acknowledge that even acute therapeutic CKI induction has
been associated with a sizable therapeutic effect in experimental stroke (17).
Human atherosclerosis is also associated with aging.
Therefore, it is characterized by senescence of vascular
smooth muscle cells, inhibition of telomerase, and telomere
shortening (18). Although González-Navarro et al. (8)
could not find evidence of senescence in the model of
p19ARF/apoE-deficient mice, it has been consistently shown
that p16INK4A is up-regulated in senescent human atherosclerotic lesions (18). Inhibition of p38 MAP kinase can
block the induction of p16INK4A and cellular senescence in
proliferative endothelial progenitor cells (EPCs) (19). Nothing is known so far about the effect of p19ARF on cellular
senescence in atherosclerosis; however, studies in bonemarrow-derived pre–B cells and macrophages suggest that
p19ARF can oppose the pro-senescent effects of p16INK4A (20).
In summary, CKIs are increasingly recognized as linking
elements among genetic susceptibility, inflammation, proliferation, apoptosis, and senescence in atherosclerosis (Fig.
1B). Their careful evaluation, albeit still at an early stage,
will possibly enable the identification of novel treatment
opportunities to combat one of the most relevant diseases of
modern times.
Acknowledgment
The author wishes to thank Ludger Hengst, PhD, University of Innsbruck, Austria, for his comments regarding the
manuscript.
Reprint requests and correspondence: Prof. Dr. Rainer Wessely,
Evangelisches Bethesda-Johanniter-Klinikum, Department of
Cardiology and Angiology, Kreuzacker 1-7, 47226 Duisburg,
Germany. E-mail: [email protected].
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Key Words: ARF y CDKN2A y atherosclerosis y apoptosis.