Ambient PM2.5 caused cardiac dysfunction through FoxO1-targeted cardiac hypertrophy and macrophage-activated fibrosis in mice

Su, Xuan; Tian, Junzhi; Li, Binghua; Zhou, Lixiao; Kang, Hui; Pei, Zijie; Zhang, Mengyue; Li, Chen; Wu, Mengqi; Wang, Qian; Han, Bin; Chu, Chen; Pang, Yaxian; Ning, Jie; Zhang, Boyuan; Niu, Yujie; Zhang, Rong

doi:10.1016/j.chemosphere.2020.125881

Cited by 57 publications

(30 citation statements)

References 57 publications

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“…38,39 In line with other studies, our data indicated that exposed to PM 2.5 caused a significant decrease in both EF and FS. 12 Left ventricular mass is an important marker for left ventricular dysfunction. In our study, an elevated left ventricular mass was observed in PM 2.5 -exposed group (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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Melatonin ameliorates PM_2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

Jiang

Liang

Zhang

et al. 2020

Journal of Pineal Research

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Fine particulate matter (PM 2.5) exposure is correlated with the risk of developing cardiac fibrosis. Melatonin is a major secretory product of the pineal gland that has been reported to prevent fibrosis. However, whether melatonin affects the adverse health effects of PM 2.5 exposure has not been investigated. Thus, this study was aimed to investigate the protective effect of melatonin against PM 2.5-accelerated cardiac fibrosis. The echocardiography revealed that PM 2.5 had impaired both systolic and diastolic cardiac function in ApoE-/mice. Histopathological analysis demonstrated that PM 2.5 induced cardiomyocyte hypertrophy and fibrosis, particularly perivascular fibrosis. While the melatonin administration was effective in alleviating PM 2.5-induced cardiac dysfunction and fibrosis in mice. Results of electron microscopy and confocal scanning laser microscope confirmed that melatonin had restorative effects against impaired mitochondrial ultrastructure and augmented mitochondrial ROS generation in PM 2.5-treated group. Further investigation revealed melatonin administration could significantly reverse the PM 2.5-induced phenotypic modulation of cardiac fibroblasts into myofibroblasts. For the first time, our study found that melatonin effectively alleviates PM 2.5-induced cardiac dysfunction and fibrosis via inhibiting mitochondrial oxidative injury and regulating SIRT3-mediated SOD2 deacetylation. Our findings indicate that melatonin could be a therapy medicine for prevention and treatment of air pollution associated cardiac diseases.

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Section: Discussionmentioning

confidence: 99%

“…10 Consistently, several studies that show PM 2.5 exposure induced cardiac phenotypic changes involved cardiac fibrosis, cardiac hypertrophy, cardiomyocyte apoptosis, inflammatory reaction, etc. 11,12 Notwithstanding, there have been only limited data suggest the underlying mechanism of PM 2.5 -induced cardiac injury.…”

mentioning

confidence: 99%

Melatonin ameliorates PM_2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

Jiang

Liang

Zhang

et al. 2020

Journal of Pineal Research

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“…In contrast, Akt2 ablation prevents aging of the heart, and its mechanism is mainly via restoration of FoxO1‐related autophagy and mitochondrial integrity 37 . Cardiac hypertrophy and fibrosis developed in mice exposed to ambient particulate matter (PM2.5), and the mechanism may be related to the PI3K/Akt/FoxO1 signal 38 . Thus, FoxO1 plays an important role in regulating myocardial hypertrophy by regulating the PI3K/Akt pathway.…”

Section: Role and Molecular Mechanism Of Foxo1 In Cardiac Hypertrophymentioning

confidence: 99%

The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy

Chen

Cheng

2020

ESC Heart Failure

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Cardiac hypertrophy can lead to heart failure and cardiovascular events and has become a research hotspot in the field of cardiovascular disease. Despite extensive and in-depth research, the pathogenesis of cardiac hypertrophy is far from being fully understood. Increasing evidence has shown that the transcription factor forkhead box protein O 1 (FoxO1) is closely related to the occurrence and development of cardiac hypertrophy. This review summarizes the current literature on the role and molecular mechanism of FoxO1 in cardiac hypertrophy. We searched the database MEDLINE via PubMed for available evidence on the effect of FoxO1 on cardiac hypertrophy. FoxO1 has many effects on multiple diseases, including cardiovascular diseases, diabetes, cancer, aging, and stem cell activity. Recent studies have shown that FoxO1 plays a critical role in the development of cardiac hypertrophy. Evidence for this relationship includes the following. (i) FoxO1 can regulate cardiac growth/protein synthesis, calcium homeostasis, cell apoptosis, and autophagy and (ii) is controlled by several upstream signalling molecules (e.g. phosphatidylinositol 3-kinase/Akt, AMP-activated protein kinase, and sirtuins) and regulates many downstream transcription proteins (e.g. ubiquitin ligases muscle RING finger 1/muscle atrophy F-box, calcineurin/nuclear factor of activated T cells, and microRNAs). In response to stress or external stimulation (e.g. low energy, oxidative stress, or growth factor signalling), FoxO1 undergoes post-translational modification and transfers from the cytoplasm to nucleus, thus regulating the expression of a series of target genes in myocardium that are involved in cardiac growth/protein synthesis, calcium homeostasis, cell apoptosis, and autophagy. (iii) Finally, targeted regulation of FoxO1 is an effective method of intervening in myocardial hypertrophy. The information reviewed here should be significant for understanding the roles of FoxO1 in cardiac hypertrophy and should contribute to the design of further studies related to FoxO1 and the hypertrophic response. It should also shed light on a potential treatment for cardiac hypertrophy.

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“…Traditional animal models of PM exposure typically use intratracheal instillation, which changes both the physical and chemical properties of particulate matter. To represent realambient exposure, our study used a real-ambient exposure system that almost completely simulates the real-ambient exposure to PM 2.5 under outdoor atmospheric PM 2.5 pollution (Jiang et al, 2020a;Su et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2−/−

Ding

Jiang

et al. 2021

Front. Pharmacol.

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Previous studies have shown that long-term exposure to fine particulate matter (PM2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2−/− (KO) mice were exposed to the real-ambient system for six weeks. After PM2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2−/− mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure. Nrf2 facilitates lung injury during PM2.5 exposure and CYP2E1 metabolism is involved in this process.

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Ambient PM2.5 caused cardiac dysfunction through FoxO1-targeted cardiac hypertrophy and macrophage-activated fibrosis in mice

Cited by 57 publications

References 57 publications

Melatonin ameliorates PM_2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

Melatonin ameliorates PM_2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2−/−

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Ambient PM2.5 caused cardiac dysfunction through FoxO1-targeted cardiac hypertrophy and macrophage-activated fibrosis in mice

Cited by 57 publications

References 57 publications

Melatonin ameliorates PM2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

Melatonin ameliorates PM2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2−/−

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Melatonin ameliorates PM_2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis

Melatonin ameliorates PM_2.5‐induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis