Macrophage-Derived Angiopoietin-Like Protein 2 Accelerates Development of Abdominal Aortic Aneurysm

Tazume, Hirokazu; Miyata, Keishi; Tian, Zhe; Endo, Motoyoshi; Horiguchi, Haruki; Takahashi, Otowa; Horio, Eiji; Tsukano, Hiroto; Kadomatsu, Tsuyoshi; Nakashima, Yukiko; Kunitomo, Ryuji; Kaneko, Yasushi; Moriyama, Shuji; Sakaguchi, Hisashi; Okamoto, Ken; Hara, Masahiko; Yoshinaga, Takashi; Yoshimura, Kenichi; Aoki, Hiroki; Araki, Kimi; Hao, Hiroyuki; Kawasuji, Michio; Oike, Yuichi

doi:10.1161/atvbaha.112.247866

Cited by 98 publications

(109 citation statements)

References 40 publications

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“…Our previous report showing chronic inflammation in skin tissue of K14-Angptl2 Tg mice demonstrated infiltration of skin tissue by inflammatory cells, including activated macrophages and neutrophils (7), both of which are sources of ROS (36). Angptl2 reportedly activates NFkB proinflammatory signaling in various cell types (3)(4)(5)(6)(7)37), which also enhances ROS production (38). Taken together, Angptl2 secreted from skin tissue of K14-Angptl2 Tg mice may increase ROS production due to activity of infiltrated and activated inflammatory cells.…”

Section: Discussionmentioning

confidence: 93%

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.

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Section: Discussionmentioning

confidence: 93%

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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“…In addition, we reported that 9 months of CAT magnified 50-folds the rise in COX2 expression associated with aging in the mouse aorta [26]. Angptl2, on the other hand, is associated with inflammation as its presence is increased in patients with rheumatoid arthritis and abdominal aortic aneurysm [47,69], while its deletion can lower pro-inflammatory cytokines in rodents [67,69]. Hence, our results suggest that early CAT treatment induces a pro-inflammatory environment upon the challenge of a WD: we propose that CAT limited the development of antioxidant defense mechanisms able to counteract the stress induced by the WD.…”

Section: Inflammationmentioning

confidence: 96%

Postnatal exposure to voluntary exercise but not the antioxidant catechin protects the vasculature after a switch to an atherogenic environment in middle-age mice

Leblond

Nguyen

Bolduc

et al. 2013

Pflugers Arch - Eur J Physiol

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We aimed to evaluate the lasting functional imprinting of exercise (EX) and catechin (CAT) on the vascular function of middle-age mice switched to a proatherogenic environment. C57BL/6J mice (n=10-15 in each group) fed a regular diet (RD) were exposed from the age of 1 to 9 months either to EX (voluntary running; 2.7± 0.2 km/day), to the polyphenol CAT (30 mg/kg/day in drinking water), or to physical inactivity (PI). At 9 months of age, EX and CAT were stopped and mice either remained on the RD or were fed a Western diet (WD) for an additional 3 months. At 12 months of age, mice from all groups fed a WD had similar body mass, systolic blood pressure, and plasma total cholesterol, glucose, insulin, and isoprostane. Compared to the RD, the WD induced an indomethacin-sensitive aortic endothelium-dependent and independent dysfunction in PI mice (p<0.05) that was prevented by both EX and CAT; this benefit was associated with a higher (p< 0.05) non-nitric oxide/non-prostacyclin endothelium-dependent relaxation. While EX, but not PI or CAT, prevented vascular dysfunction induced by the WD in cerebral arteries, it had no effect in femoral arteries. The profiles of activity of antioxidant enzymes and of proinflammatory gene expression in the aorta suggest a better adaptation of EX>CAT>PI mice to stress. In conclusion, our data suggest that a postnatal exposure to EX, but not to CAT, imprints an adaptive defense capacity in the vasculature against a deleterious change in lifestyle.Correspondence to: Eric Thorin.eric.thorin@umontreal.ca. Electronic supplementary material The online version of this article

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“…ANGPTL2 and Heart Disease secreted ANGPTL2 also accelerates atherosclerotic disease in mice (Figure 4). 55 Thus, ANGPTL2-induced chronic inflammation predisposes individuals to atherosclerotic disease and to CAD development. Furthermore, inflammation also underlies plaque destabilization.…”

Section: Angptl2 Function In Obesity and Associated Metabolic Diseasesmentioning

confidence: 99%

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

Oike

Tian

Miyata

et al. 2017

Circ J

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inflammation, 11,12 and emerging evidence reveals that senescent cells secrete factors that cause chronic local tissue inflammation associated with age-associated diseases. [13][14][15] This newly identified cellular senescence condition, termed the senescence-associated secretory phenotype (SASP), is now recognized as creating a common pathological environment that encourages development of age-associated diseases, including CVD. 13,15, 16 Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. 17-21 ANGPTL2 expression also increases in cells undergoing senescence, 22 suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. 23-25 Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD. What Is ANGPTL2?Around 2000, several groups independently reported secreted glycoproteins that exhibit an N-terminal coiled-coil W orldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's wellbeing and productivity. 1,2 Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle.The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; 3 thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. 4,5 However, these events continue to occur, even in patients whose LDLcholesterol levels have been lowered by antidyslipidemia treatment, 1,2,4,5 indicating that the pathologies underlying CVD are highly complex. In addition to dyslipidemia, other factors such as smoking, hypertension, diabetes, ventral obesity, male sex, aging, genetic factors, and family history of CVD are well-established risk factors, 6-8 and the number of patients with dyslipidemia, diabetes, and hypertension also increases with age. 9 Recently, it was shown that chronic vascular inflammation accelerates atherosclerosis development. 10 Interestingly, aging, smoking, diabetes, and dyslipidemia all induce chronic In parallel with the increase in the number of elderly people worldwide, the number of patients with heart disease is also rapidly increasing. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are strongly associated with adverse health outcomes that decrease productivity in later years. Recently, ANGPTL2, a secreted glycoprotein and member of the angiopoietin-like protein family, has received attention as a causal player in the development of CVD and HF. Prolonged ANGPTL2 auto...

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Macrophage-Derived Angiopoietin-Like Protein 2 Accelerates Development of Abdominal Aortic Aneurysm

Cited by 98 publications

References 40 publications

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Postnatal exposure to voluntary exercise but not the antioxidant catechin protects the vasculature after a switch to an atherogenic environment in middle-age mice

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

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Macrophage-Derived Angiopoietin-Like Protein 2 Accelerates Development of Abdominal Aortic Aneurysm

Cited by 98 publications

References 40 publications

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Postnatal exposure to voluntary exercise but not the antioxidant catechin protects the vasculature after a switch to an atherogenic environment in middle-age mice

ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

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ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―