Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE −/− mice

Cong, Guangzhi; Yan, Rong; Huang, Hui; Wang, Kai; Ning, Yan; Park, Jin; Zhang, Na; Hou, Jianjun; Chen, Dapeng; Jia, Shanshan

doi:10.1016/j.lfs.2017.02.003

Cited by 21 publications

(17 citation statements)

References 47 publications

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“…The inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro . In conclusion, HHcy‐induced macrophage apoptosis mediates the progression of atherosclerosis, and histone methylation attributed to HHcy may be involved in this process (Cong et al ., ).…”

Section: The Mechanisms Of Vascular Injury Induced By Hhcymentioning

confidence: 97%

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Wang

Kong

2017

British J Pharmacology

104

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Section: The Mechanisms Of Vascular Injury Induced By Hhcymentioning

confidence: 97%

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Wang

Kong

2017

British J Pharmacology

104

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“…group, including male and female, and were fed with following diets (KeAoXieLi, Beijing, China) for 30 weeks: the control group ate a standard rodent maintenance diet-93 purified diet (AIN-93G) as recommended by the American Institute of Nutrition and the hypermethionine group ate a chow diet plus a methionine-containing diet (17 g/kg) (13,14). Random selection and blinding methods were used for the selection of experimental animal.…”

Section: Hhcy Induces Vascular Calcification Via Klf4 Up-regulationmentioning

confidence: 99%

“…Hyperhomocysteinemia (Hhcy) 2 is closely linked to atherosclerosis and is one of the risk factors of atherosclerosis (11,12). We and others have reported that Hhcy promotes atherosclerosis via promoting macrophage apoptosis (13,14), inhibiting endothelial cell growth (15), and promoting inflammatory monocyte differentiation (16). Studies have shown that Hcy significantly increases oxidative stress via up-regulation of NOX4 and NOX2 in endothelial cells (17), and Hcy significantly up-regulates the expression of NOX4 in adventitial fibroblasts in vitro (18).…”

mentioning

confidence: 99%

Hyperhomocysteinemia induces vascular calcification by activating the transcription factor RUNX2 via Krüppel-like factor 4 up-regulation in mice

Zhu

Zhang

Yan

et al. 2019

Journal of Biological Chemistry

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Edited by Qi-Qun Tang One of the main characteristics of atherosclerosis is vascular calcification, which is linked to adverse cardiovascular events. Increased homocysteine (Hcy), a feature of hyperhomocysteinemia, is correlated with advanced vascular calcification and phenotypic switching of vascular smooth muscle cells (VSMCs). Oxidative stress and high phosphate levels also induce VSMC calcification, suggesting that the Krüppel-like factor 4 (KLF4) signaling pathway may also contribute to vascular calcification. In this study, we investigated this possibility and the role and mechanisms of Hcy in vascular calcification. We found that in atherosclerotic apolipoprotein E-deficient (ApoE ؊/؊) mice, Hcy significantly increases vascular calcification in vivo, as well as VSMC calcification in vitro. Of note, the Hcy-induced VSMC calcification was correlated with elevated KLF4 levels. Hcy promoted KLF4 expression in calcified atherosclerotic lesions in vivo and in calcified VSMCs in vitro. shRNA-mediated KLF4 knockdown blocked the Hcy-induced up-regulation of runt-related transcription factor 2 (RUNX2) and VSMC calcification. RUNX2 inhibition abolished Hcy-induced VSMC calcification. Using ChIP analysis, we demonstrate that KLF4 interacts with RUNX2, an interaction promoted by Hcy stimulation. Our experiments also revealed that the KLF4 knockdown attenuates Hcy-induced RUNX2 transactivity, indicating that KLF4 is important in modulating RUNX2 transactivity. These findings support a role for Hcy in regulating vascular calcification through a KLF4-RUNX2 interaction and indicate that Hcy-induced, enhanced RUNX2 transactivity increases VSMC calcification. These insights reveal possible opportunities for developing interventions that prevent or manage vascular calcification. Atherosclerosis increases the occurrence of peripheral vascular disease, cerebral infarction, and coronary heart disease. Among its characteristics, arterial calcification is the most common feature (1-7). Abnormal deposition of hydroxyapatite mineral in the arteries leads to arterial wall thickening and

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“…Much evidence has accrued that the apoptosis of macrophages can influence the stability of atherosclerotic plaques (25,47). Macrophage apoptosis intensifies the formation of plaque necrotic cores, causes thinning of the fibrous cap, and ultimately leads to PR (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway

Fang

Sun

Cai

et al. 2021

Preprint

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Acute coronary syndrome (ACS) caused by plaque rupture (PR) is the chief culprit behind cardiovascular death, yet its exact mechanism remains unclear. Immunity-related GTPase (IRGM/Irgm1) has been widely studied in several inflammatory diseases, but the role of IRGM/Irgm1 in atherosclerosis is poorly characterized. Here, we shed light on the mechanism by which IRGM/Irgm1 contributes to plaque vulnerability in atherosclerosis. We first identified ruptured and non-ruptured plaques by optical coherence tomography, and strikingly found that serum IRGM was highly expressed in ST-segment elevation myocardial infarction patients with PR. Next, we used ApoE-/-Irgm1+/+ and ApoE-/-Irgm1+/- mice and corresponding bone marrow chimeras to establish a model for advanced atherosclerosis, and found that Irgm1 could aggravate progression of atherosclerotic plaques. We confirmed that Irgm1 contributes to macrophage apoptosis by promoting the production of reactive oxygen species. Finally, we discovered that Irgm1 induces macrophage apoptosis by activating the MAPK signaling pathway. Our findings highlight the mechanism by which IRGM/Irgm1 contributes to the formation of vulnerable plaques and may offer a novel target for the timely treatment of ACS.

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Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE −/− mice

Cited by 21 publications

References 47 publications

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Hyperhomocysteinemia induces vascular calcification by activating the transcription factor RUNX2 via Krüppel-like factor 4 up-regulation in mice

IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway

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