Angiopoietin‐Like 2 Promotes Atherogenesis in Mice

Farhat, Nada; Thorin‐Trescases, Nathalie; Mamarbachi, Maya; Villeneuve, Louis; Yu, Carol; Martel, Cécile; Duquette, Natacha; Gayda, Mathieu; Nigam, Anil; Juneau, Martin; Allen, Bruce G.; Thorin, Éric

doi:10.1161/jaha.113.000201

Cited by 57 publications

(111 citation statements)

References 39 publications

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“…In two recent reports, it was shown that angptl2 promoted endothelial dysfunction in a pro-atherogenic environment, decreased relaxation and expression of phosphoeNOS (20), increased leukocytes adhesion, and ultimately accelerated atherogenesis (12). Our demonstration that knockdown of angptl2 favors NO-dependent dilation in cerebral arteries therefore suggests that angptl2 plays a role in reducing endothelial cell stress resistance.…”

Section: Discussionsupporting

confidence: 56%

“…In addition, knockdown of angptl2 may be associated with beneficial effects of a Nox, likely Nox4, an isoform that predominantly produces dilatory H 2 O 2 . Taken together, preventing the demonstrated rise of angptl2 through age (20) and atherosclerosis (12,20) may emerge as a new therapeutic concept to increase endothelial cell stress resistance and delay atherogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Mice were anesthetized and maintained throughout the procedure by inhalation of isoflurane (1-3% mixed with 97% O 2). For 3 wk before subcutaneous implantation, mice were trained by tail-cuff plethysmography (Kent Scientific, Torrington, CT) with baseline recording and during the 14 days of subcutaneous treatment, blood pressure (systolic, diastolic, and mean arterial pressures) and heart rate were noninvasively recorded on days 5,10,12, and 14 as previously described (3). For reference, blood pressure was also assessed under anesthesia by both Millar catheter and tail-cuff.…”

Section: Animalsmentioning

confidence: 99%

“…Recently, a protein identified as angiopoietin like-protein 2 (angptl2), a member of the greater angiopoietin-like family and derived from various cell types including adipocytes (31) and endothelial cells (12), has been implicated in a number of chronic inflammatory disorders such as insulin resistance (31), atherosclerosis (12), and tumor progression (1,34). On the other hand, upregulation of angptl2 gene expression, among other genes, was recently reported in the aged brain of both rats and human, contributing to poststroke angiogenesis (5).…”

mentioning

confidence: 99%

“…There is no report on cerebral endothelial function, and the specific impact of angptl2 on the regulation of endothelial-derived relaxing factors (EDRFs) is only emerging (40). Through its pro-inflammatory (12,31) and its pro-oxidative effects (2), we hypothesized that angptl2 contributes to cerebral endothelial dysfunction and the modulation of the EDRFs and that knockdown of angptl2 would increase endothelial cell stress resistance in mouse arteries. To test this hypothesis, we induced endothelial stress by chronic (14 days) infusion of a low dose of ANG II in angptl2 KD mice.…”

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confidence: 99%

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Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

Luo

Duquette

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng·kg Ϫ1 ·min Ϫ1 , n ϭ 15) or saline (n ϭ 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O 2 Ϫ /H2O2 contributed to dilation in WT mice, eNOS-derived NO (P Ͻ 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice (P Ͻ 0.05), which was reversed (P Ͻ 0.05) by either N-acetyl-L-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactive oxygen species from Nox2 and Cox-derived contractile factors. In KD mice treated with ANG II, endothelial function was preserved, likely via Nox-derived H 2O2, sensitive to apocynin and PEG-catalase (P Ͻ 0.05), but not to gp91ds-tat. In the aorta, relaxation similarly and essentially depended on NO; endothelial function was maintained after ANG II infusion in all groups, but apocynin significantly reduced aortic relaxation in KD mice (P Ͻ 0.05). Protein expression levels of Nox1/2 in cerebral arteries were similar among all groups, but that of Nox4 was greater (P Ͻ 0.05) in saline-treated KD mice. In conclusion, knockdown of angptl2 may be protective against ANG II-induced cerebral endothelial dysfunction; it favors the production of NO, likely increasing endothelial cell resistance to stress, and permits the expression of an alternative vasodilatory Nox pathway.angiopoietin like-2; endothelium; cerebral arteries; nitric oxide; NA-DPH oxidases CARDIOVASCULAR DISEASES, INCLUDING stroke, affect more than 50% of the world population today and remain an unresolved clinical issue. Inflammation and oxidative stress synergize to promote endothelial damage, thereby chronically driving atherogenesis (13,14). Importantly, the cerebral vascular endothelium is highly sensitive to this deleterious environment (8, 11). Reactive oxygen species (ROS) are signaling molecules generated by the electron transport chain (35) and are by-products of enzymes including the NADPH oxidases (18), xanthine oxidases, and uncoupled endothelial nitric oxide (NO) synthase (eNOS) (19,28). In parallel, they trigger an innate anti-oxidative system to prevent their potential harmful effects (26,29). When this system is overwhelmed, however, endothelial damages occur and dysfunction develops, which are the first steps toward atherogenesis.Recently, a protein identified as angiopoietin like-protein 2 (angptl2), a member of the greater angiopoietin-like family and derived from various cell types including adipocytes (31) and endothelial cells (12), has been implicated in a number of chronic inflammatory d...

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

Luo

Duquette

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Incidence of cardiovascular disease in a cohort of mine workers exposed to ultrafine aluminum powder in Ontario, Canada

Zarnke,

Rhodes,

DeBono

et al. 2024

American J Industrial Med

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BackgroundA retrospective cohort study was conducted to estimate associations between an ultrafine aluminum powder, McIntyre Powder (MP), and cardiovascular disease incidence in a cohort of mine workers from Ontario, Canada. Disease outcomes included ischemic heart disease (IHD), acute myocardial infarction (AMI), congestive heart failure (CHF), and strokes and transient ischemic attacks (STIA).MethodsUsing work history records from the Ontario Mining Master File (MMF) mine workers were followed for disease incidence in administrative health records. The analysis included 25,813 mine workers who were exposed to MP between 1943 and 1979 and followed for cardiovascular disease (CVD) diagnoses between 2006 and 2018. Cardiovascular disease cases were ascertained using physician, hospital, and ambulatory care records. Poisson regression models were used to estimate age and birth‐year adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) for associations between MP exposure and CVD outcomes.ResultsEver‐exposure to MP was positively associated with modest increases in the incidence rate of IHD, AMI, and CHF, but not STIA, using both assessment approaches. Duration of self‐reported MP exposure was positively associated with monotonically increasing rates of IHD and AMI compared to never‐exposed miners, with the greatest association observed among miners with >20 years of exposure (for IHD: RR 1.24, 95% CI: 0.91–1.68; and for AMI: RR 1.52, 95% CI 1.01–2.28).ConclusionMine workers ever‐exposed to MP had modestly elevated rates of CVD. The rate of CVD diagnoses appeared to increase with longer duration of exposure when assessed by both self‐reported exposure and through historical records.

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Preliminary study of the relationship between promoter methylation of the ANGPTL2 gene and coronary heart disease

Zhou

Chen

et al. 2018

Clinical Laboratory Analysis

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Background Coronary heart disease (CHD) is primarily caused by atherosclerosis of coronary arteries. It is largely an inflammatory disease of the vascular wall. The inflammation is related to DNA methylation. Angiopoietin‐like protein 2 (ANGPTL2) has various functions in several chronic inflammatory diseases. Macrophage‐derived ANGPTL2 was reported to accelerate CHD development. It is reported that DNA hypomethylation in the promoter region of ANGPTL2 gene was associated with acute coronary syndrome (ACS), a type of CHD. Our objective was to explore the correlation between promoter methylation of the ANGPTL2 gene and CHD, and to investigate the association between methylation status and clinical characteristics of CHD patients. Methods Firstly, we collected 122 CHD patients and 58 non‐CHD participants from Han Chinese population and purified the peripheral blood DNA. The purified DNA was subjected to bisulfite modification. After bisulfite conversion, the target DNA locus was amplified using polymerase chain reaction (PCR), and the PCR products were measured by pyrosequencing. Finally, the methylation level was calculated according to the sequencing result, and the data were analyzed using xx software. Results CHD patients had a relatively lower methylation levels (P50: 7.67% [P25: 6.22%, P75: 10.43%]) in the ANGPTL2 promoter region than did controls (P50: 8.25% [P25: 5.46%, P75: 17.98%], P = 0.001), indicating an association between ANGPTL2 promoter methylation and CHD (OR: 0.890; 95% CI, 0.832‐0.953; adjusted P = 0.001). A breakdown analysis by gender showed that ANGPTL2 promoter methylation was associated with CHD in females (adjusted P = 0.002) but not in males (adjusted P = 0.404). We found no correlation between gene methylation and other clinical characteristics. Conclusions The present work provides evidence to support an association between ANGPTL2 promoter DNA methylation status and the risk profile of CHD in females. Our data indicated that in females, promoter DNA hypomethylation of the ANGPTL2 gene is associated with an increased risk of CHD.

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Angiopoietin‐Like 2 Promotes Atherogenesis in Mice

Cited by 57 publications

References 39 publications

Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

Incidence of cardiovascular disease in a cohort of mine workers exposed to ultrafine aluminum powder in Ontario, Canada

Preliminary study of the relationship between promoter methylation of the ANGPTL2 gene and coronary heart disease

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