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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 2270 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]. REFERENCES 1. Wessely R, Schömig A, Kastrati A. Sirolimus and paclitaxel on polymer-based drug-eluting stents: similar but different. J Am Coll Cardiol 2006;47:708 –14. 2. Buss SJ, Muenz S, Riffel JH, et al. Beneficial effects of mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol 2009;54:2435– 46. 3. Raichlin E, Bae J-H, Khalpey Z, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft JACC Vol. 55, No. 20, 2010 May 18, 2010:2269–71 4. 5. 6. 7. 8. 9. 10. 11. 12. vasculopathy after cardiac transplantation. 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The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo. Nat Med 1999;5:335–9. Boesten LSM, Zadelaar ASM, van Nieuwkoop A, et al. Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice. FASEB J 2006;20:953–5. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science 2007; 316:1488 –91. Wessely Atherosclerosis and Cell Cycle 2271 13. Schunkert H, Gotz A, Braund P, et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation 2008;117:1675– 84. 14. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. 15. Rossi AG, Sawatzky DA, Walker A, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 2006;12:1056 – 64. 16. Andres V. Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential. Cardiovasc Res 2004;63:11–21. 17. Osuga H, Osuga S, Wang F, et al. Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci U S A 2000;97: 10254 –59. 18. Matthews C, Gorenne I, Scott S, et al. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 2006;99:156 – 64. 19. Zhang Y, Herbert B-S, Rajashekhar G, et al. Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor-{alpha} via the p38 mitogen-activated protein kinase pathway. FASEB J 2009;23:1358 – 65. 20. Randle DH, Zindy F, Sherr CJ, Roussel MF. Differential effects of p19ARF and p16INK4A loss on senescence of murine bone marrowderived preB cells and macrophages. Proc Natl Acad Sci U S A 2001;98:9654 –9. Key Words: ARF y CDKN2A y atherosclerosis y apoptosis.