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Senescent intimal foam cells are deleterious at all stages of atherosclerosis

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Science  28 Oct 2016:
Vol. 354, Issue 6311, pp. 472-477
DOI: 10.1126/science.aaf6659

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  • How hypertension induces atherosclerosis
    • Qiuyun Liu, Professor, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Sun Yat-sen University
    • Other Contributors:
      • Xiaoxia Li, Researcher, School of Materials Science and Engineering, Sun Yat-Sen University, China
      • Du Cheng, Professor, School of Materials Science and Engineering, Sun Yat-Sen University, China
      • Zhenlang Chen, Researcher, Shanghai Links Med-technology Co., Ltd, Shanghai, China
      • Liang Cui, student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Zhixue Wang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    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
    ri...

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    Competing Interests: None declared.
  • RE: Childs et al: Senescent intimal foam cells are deleterious at all stages of atherosclerosis
    • Martin Richard Bennett, BHF Professor of Cardiovascular Sciences, University of Cambridge
    • Other Contributors:
      • Murray Charles Henry Clarke, BHF Senior Research Fellow, University of Cambridge

    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).

    Thu...

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    Competing Interests: None declared.
  • RE: Childs et al: Senescent intimal foam cells are deleterious at all stages of atherosclerosis
    • Martin R Bennett, BHF Professor of Cardiovascular Sciences, University of Cambridge
    • Other Contributors:
      • Murray H C Clarke, BHF Senior Research Fellow, University of Cambridge

    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 fea...

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    Competing Interests: None declared.