Senescent intimal foam cells are deleterious at all stages of atherosclerosis
Wreaking havoc while (growth-)arrested
Cells enter a state of senescence in response to certain stresses. Studying mouse models, Childs et al. examined the role of senescent lipid-loaded macrophages (so-called “foam cells”) in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease.
Science, this issue p. 472
Abstract
Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor–deficient (Ldlr–/–) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.
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Published In
Science
Volume 354 | Issue 6311
28 October 2016
28 October 2016
Copyright
Copyright © 2016, American Association for the Advancement of Science.
Submission history
Received: 11 March 2016
Accepted: 29 September 2016
Published in print: 28 October 2016
Acknowledgments
We thank R.-M. Laberge and M. Demaria for sharing data on the senolytic properties of ABT263, as well as N. David, Y. Poon, M. Hofker, B. van de Sluis, and the van Deursen lab for helpful discussions. This work was supported by a grant from the Paul F. Glenn Foundation (to J.M.v.D. and D.J.B.) and NIH grants R01CA96985 and CA168709 (to J.M.v.D.). J.M.v.D. and J.C. are cofounders of Unity Biotechnology, a company developing senolytic medicines including small molecules that selectively eliminate senescent cells. J.M.v.D., D.J.B., B.G.C., and J.C. are co-inventors on patent applications licensed to or filed by Unity Biotechnology. The p16-3MR mice are available from J.C. under a material transfer agreement. INK-ATTAC and INK-NTR mice are available from J.M.v.D. under a material transfer agreement.
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How hypertension induces atherosclerosis
Hypertension contributes significantly to a number of diseases and conditions such as
heart failure, stroke, coronary artery disease, etc. Atherosclerosis is characterized by
the hardening of the arteries (1). One hallmark of the disease is the deposit of calcium
and other crystallized materials within the plaque, and extracellular calcium buildup
between the muscular wall and outer section of the atheromatous plaques (2).
Angiotensins II, III and IV are direct vasoconstrictors increasing blood pressure (3).
GPCR AT1 is involved in this process by activating Phospholipase C, resulting in the
increase of intracellular calcium level.
As hypertension causes the rise of calcium level, insoluble and rigid salts are formed
between calcium and organic acids, phosphate, etc., which damages cells and
contributes to atherosclerosis. Weak acids can help dissolve insoluble salts. Food of
aquatic origin such as fish is rich in hydrogen bond donors and acceptors which
enhance proton traffic and formation of weak acids. However, the simultaneous
presence of hydrogen bond donors and acceptors and high content of basic amino
acids need to be avoided as they collectively build up strong acids and are
carcinogenic (4).
Krebs cycle is a major source of protons and organic acids such as oxalate. Numerous
organic acids have modest median lethal doses on animals, and form insoluble and
rigid salts with calcium. Compounds with similar structures as oxalate, for instance,
ethanol and acetic acids could extend lifespans (5-6), perhaps by the inhibition of
oxalate generation. Another structurally related compound glyoxylate is widely used
in skin care products in the elimination of age-related wrinkles. A declined respiration
chain for ATP production may appear in the elderly, and a normal Krebs cycle results
in the buildup of organic acids and insoluble salts, accounting for many age-related
diseases (7). The aforementioned hypothesis may underlie some other cardiovascular
diseases such as stroke and heart failure.
Polyunsaturated fatty acids possess σ-π hyperconjugation and electron delocalization
leading to increased affinities to cations. Therefore, some of these fatty acids can
promote cation traffic as well as the elimination of cations such as Ca 2+ , a beneficial
feature in numerous circumstances for age-related diseases when they are rich in food
(8).
Xiaoxia Li, 2,4 Du Cheng, 2,4 Zhenlang Chen, 3,4 Liang Cui, 1 Zhixue Wang, 1
Qiuyun Liu, 1*
1 Guangdong Provincial Key Laboratory of Improved Variety Reproduction in
Aquatic Economic Animals, Biomedical Center, State Key Laboratory of Biocontrol,
Lab of Microbial Metabolic Engineering and Synthetic Biology, Lab for Earthquake
Perception Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou
510275, China.
2 School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou
510275, China.
3 Shanghai Links Med-technology Co., Ltd, Shanghai, China.
4 Equal contributions.
*Correspondence author.
E-mail address: [email protected] (Q. Liu)
References:
1. S. Seely, Int J Cardiol 22, 5 (1989).
2. N. Stadler et al., Arterioscler Thromb Vasc Biol 28, 1024 (2008).
RE: Childs et al: Senescent intimal foam cells are deleterious at all stages of atherosclerosis
Dear Dr Berg
We wish to offer an alternative interpretation of some surprising data in the recent Childs et al paper(1). The authors identify senescent cells using the lysosomal marker senescence-associated beta galactosidase (SAβG) and 'canonical' senescence-associated secretory phenotype (SASP) markers. They show that senescent cells comprise a high % of cells in ldl-receptor-null mouse atherosclerotic plaques, occur within 9 days of fat feeding, and can be selectively ablated using p16 promoter activity, although their precise lineage and whether these cells were also dividing were not determined.
In contrast, recent studies have shown that SAβG is not specific for senescent cells in mice but also marks macrophages(2), and the 'canonical' SASP markers used by the authors such as MMPs, TNFα and IL1α can also be expressed by macrophages. p16ink4a is expressed in resident and inflammatory macrophages, including in human atherosclerotic plaques(3,4), is upregulated when monocytes differentiate into macrophages(3) and can regulate their polarization(5), whilst p16ink4a deficiency results in decreased inflammatory signaling in murine macrophages. Furthermore, phagocytic cells comprise most SAβG staining in chronologically aged mice, whilst macrophage removal reduces the p16 signal in p16 reporter mice(2). Ablation of monocyte/macrophages can reduce plaque development and promote features of plaque stability, particularly in less advanced lesions(6).
Thus, an alternative explanation is that 'inflammatory' macrophages are present at all stages of atherosclerosis and express SAβG activity and SASP markers, but p16, SAβG and these SASP markers do not selectively identify senescent cells in atherosclerosis. Removal of p16+/SAβG+ macrophages would be predicted to reduce atherosclerosis. This explanation does not negate the important finding that ablation of p16+ cells, which may include these macrophages, reduces plaque development and progression, or that senolytic drugs might benefit atherosclerosis.
Yours sincerely
Martin R Bennett Murray HC Clarke
Division of Cardiovascular Medicine
University of Cambridge
Box 110, ACCI, Hills Road, Cambridge, CB2 0QQ, UK
+44 1223 331504
References
1. B. G. Childs et al., Science. 354, 472-477 (2016).
2. B. M. Hall et al., Aging. 8, 1294-1315 (2016).
3. L. Fuentes et al., Diabetologia. 54, 3150-3156).
4. L. M. Holdt et al., Atherosclerosis. 214, 264-270).
5. C. Cudejko et al., Blood. 118, 2556-2566 (2011).
6. V. Stoneman et al., Circ Res. 100, 884-893 (2007).
RE: Childs et al: Senescent intimal foam cells are deleterious at all stages of atherosclerosis
Dear Dr Berg
We wish to offer an alternative interpretation of some surprising data in the recent Childs et al paper(1). The authors identify senescent cells using the lysosomal marker senescence-associated beta galactosidase (SAβG) and 'canonical' senescence-associated secretory phenotype (SASP) markers. They report that senescent cells comprise a very high % of cells in Ldlr-null mouse atherosclerotic plaques, occur within 9 days of fat feeding, and can be selectively ablated using p16 promoter activity, although their precise lineage (smooth muscle, endothelial cell or macrophage) and whether these cells were also dividing were not determined.
In contrast, recent studies have shown that SAβG is not specific for senescent cells in mice but also marks macrophages(2), and the 'canonical' SASP markers used by the authors such as MMPs, TNFα and IL-1α can also be highly expressed by macrophages. p16ink4a is expressed in resident and inflammatory macrophages, including in human atherosclerotic plaques(3,4), is upregulated when monocytes differentiate into macrophages(3,5) and can regulate their polarization(5), whilst p16ink4a deficiency results in decreased inflammatory signaling in murine macrophages(5). Furthermore, phagocytic cells have been shown to have SAβG activity in chronologically aged mice, whilst macrophage removal reduces the p16ink4a signal in p16ink4a reporter mice(2). Ablation of monocyte/macrophages can reduce plaque development and promote features of plaque stability, particularly in less advanced lesions(6).
Thus, an alternative explanation is that 'inflammatory' macrophages are present at all stages of atherosclerosis and express SAβG activity, p16ink4a and SASP markers, but these markers do not selectively identify senescent cells in atherosclerosis. Removal of p16+/SAβG+ macrophages would be predicted to reduce atherosclerosis independently of senescence. This explanation does not negate the important finding that ablation of p16ink4a+ cells, which may include these macrophages, reduces plaque development and progression, or that senolytic drugs might benefit atherosclerosis.
Yours sincerely,
Martin R Bennett Murray HC Clarke
Division of Cardiovascular Medicine
University of Cambridge
Box 110, ACCI, Hills Road, Cambridge, CB2 0QQ, UK
+44 1223 331504
References
1. B. G. Childs et al., Science. 354, 472-477 (2016).
2. B. M. Hall et al., Aging. 8, 1294-1315 (2016).
3. L. Fuentes et al., Diabetologia. 54, 3150-3156 (2011).
4. L. M. Holdt et al., Atherosclerosis. 214, 264-270 ().
5. C. Cudejko et al., Blood. 118, 2556-2566 (2011).
6. V. Stoneman et al., Circ Res. 100, 884-893 (2007).