Fibroblast growth factor 21 attenuates hypoxia-induced pulmonary hypertension by upregulating PPARγ expression and suppressing inflammatory cytokine levels

Liu, Jingjing; Cai, Gexiang; Li, Manxiang; Fan, Shuli; Yao, Boyang; Ping, Wei-Dong; Huang, Zhifeng; Cai, Hui; Dai, Yong-Yue; Wang, Liangxing; Huang, Xiaoying

doi:10.1016/j.bbrc.2018.09.004

Cited by 29 publications

(41 citation statements)

References 26 publications

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“…As discussed above, FGF 21 appears to protect against damaging inflammation, reperfusion injury and oxidative stress when administered to cell cultures or laboratory animals [23][24][25][26] . This protective measure can be overwhelmed, and FGF 21 has been shown to predict renal injury after coronary angiography 44 , liver failure in critically ill patients with cirrhosis 45 , and poor outcome in patients with sepsis 46,47 .…”

Section: Or 95% CI P-valuementioning

confidence: 94%

“…In our patient cohort we observed elevated FGF 21 levels on ICU admission and an increase between 24 and 48 h timepoints. Interestingly, FGF 21 has been shown to play an anti-inflammatory role in sepsis 23 and hypoxia-induced pulmonary hypertension 24 and to protect myocardium 25 and neurons 26 in oxidative stress. Therefore, increasing FGF 21 levels can be interpreted to reflect a protective response to severe perturbations in oxidative metabolism.…”

Section: Or 95% CI P-valuementioning

confidence: 99%

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Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome

Pekkarinen

Skrifvars

Lievonen

et al. 2021

Sci Rep

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Fibroblast growth factor (FGF) 21 is a marker associated with mitochondrial and cellular stress. Cardiac arrest causes mitochondrial stress, and we tested if FGF 21 would reflect the severity of hypoxia-reperfusion injury after cardiac arrest. We measured serum concentrations of FGF 21 in 112 patients on ICU admission and 24, 48 and 72 h after out-of-hospital cardiac arrest with shockable initial rhythm included in the COMACARE study (NCT02698917). All patients received targeted temperature management for 24 h. We defined 6-month cerebral performance category 1–2 as good and 3–5 as poor neurological outcome. We used samples from 40 non-critically ill emergency room patients as controls. We assessed group differences with the Mann Whitney U test and temporal differences with linear modeling with restricted maximum likelihood estimation. We used multivariate logistic regression to assess the independent predictive value of FGF 21 concentration for neurologic outcome. The median (inter-quartile range, IQR) FGF 21 concentration was 0.25 (0.094–0.91) ng/ml in controls, 0.79 (0.37–1.6) ng/ml in patients at ICU admission (P < 0.001 compared to controls) and peaked at 48 h [1.2 (0.46–2.5) ng/ml]. We found no association between arterial blood oxygen partial pressure and FGF 21 concentrations. We observed with linear modeling an effect of sample timepoint (F 5.6, P < 0.01), poor neurological outcome (F 6.1, P = 0.01), and their interaction (F 3.0, P = 0.03), on FGF 21 concentration. In multivariate logistic regression analysis, adjusting for relevant clinical covariates, higher average FGF 21 concentration during the first 72 h was independently associated with poor neurological outcome (odds ratio 1.60, 95% confidence interval 1.10–2.32). We conclude that post cardiac arrest patients experience cellular and mitochondrial stress, reflected as a systemic FGF 21 response. This response is higher with a more severe hypoxic injury but it is not exacerbated by hyperoxia.

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Section: Or 95% CI P-valuementioning

confidence: 94%

Section: Or 95% CI P-valuementioning

confidence: 99%

Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome

Pekkarinen

Skrifvars

Lievonen

et al. 2021

Sci Rep

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“…Sustained hypoxia promotes the development of PAH and leads to hypoxic pulmonary hypertension (HPH; Lahm & Chakinala, 2013;J. Liu et al, 2018).…”

Section: Nox4 and Pulmonary Vascular Diseasesmentioning

confidence: 99%

The role of NOX4 in pulmonary diseases

Feng

et al. 2020

Journal Cellular Physiology

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Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a subtype of the NOX family, which is mainly expressed in the pulmonary vasculature and pulmonary endothelial cells in the respiratory system. NOX4 has unique characteristics, and is a constitutively active enzyme that primarily produces hydrogen peroxide. The signaling pathways associated with NOX4 are complicated. Negative and positive feedback play significant roles in regulating NOX4 expression. The role of NOX4 is controversial because NOX4 plays a protective or damaging role in different respiratory diseases. This review summarizes the structure, enzymatic properties, regulation, and signaling pathways of NOX4. This review then introduces the roles of NOX4 in different diseases in the respiratory system, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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“…Another factor should be taken into account is peroxisome proliferator-activated receptor gamma (PPAR-γ). Upregulation of PPAR-γ is responsible for many effects of FGF21 (Hui et al., 2016; Liu et al., 2018). Interestingly, there may be a close relationship between PPAR-γ and HSP72 because naringin upregulates PPARγ and HSP72 simultaneously (Sharma et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

FGF21 Protects Against Hypoxia Injury Through Inducing HSP72 in Cerebral Microvascular Endothelial Cells

et al. 2019

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Background: Fibroblast growth factor 21 (FGF21), a member of a family of atypical FGFs, functions as cytokine to control endocrinology and metabolism. Recently, the roles of FGF21 in cardio-cerebral-vascular diseases have been gradually uncovered. In the present study, we investigated the effect of FGF21 on bEnd.3 cerebral microvascular endothelial cells (CMECs) upon hypoxia stress. Methods and Results: CMECs were cultured in the condition of 1% O 2 for 8 h to induce hypoxia stimuli. For FGF21 treatment, recombinant FGF21 (50 nM) was added into the culture medium. Various biomedical assays were used to evaluate the hypoxia-induced injury in CMECs. Under normoxia condition, FGF21 had no obvious effect on cell viability and did not cause any cytotoxicity on CMECs. Under hypoxia condition, FGF21 significantly attenuated the hypoxia-induced injury, evidenced by the influences of FGF21 on CMEC viability and LDH release. TUNEL staining assay and immunoblotting of caspase-3 showed that FGF21 reduced hypoxia-induced apoptosis in CMECs. Mechanistically, FGF21 treatment compromised the hypoxia-induced changes of reactive oxygen species, malondialdehyde, total antioxidant activity, and total superoxide dismutase levels. FGF21 administration decreased hypoxia-induced matrix metalloprotein 3 and matrix metalloprotein 2/9 activity in CMECs. Activities of cyclooxygenase-2 and NF-κB-p65, two pro-inflammatory factors, were also upregulated by hypoxia but suppressed by FGF21. At last, we found that FGF21 increased heat shock protein family A member 1A (HSP72) mRNA and protein expression. Blockade of HSP72 by a pharmacological inhibitor VER155008 or specific siRNA-mediated knockdown abrogated the protection of FGF21 against hypoxia in CMECs. Conclusion: These data demonstrate that FGF21 protects against hypoxia stress-induced injury in CMECs by inducing HSP72 expression, suggesting a therapeutic value of FGF21 in hypoxia-related brain diseases such as ischemic stroke and acute mountain sickness.

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Fibroblast growth factor 21 attenuates hypoxia-induced pulmonary hypertension by upregulating PPARγ expression and suppressing inflammatory cytokine levels

Cited by 29 publications

References 26 publications

Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome

Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome

The role of NOX4 in pulmonary diseases

FGF21 Protects Against Hypoxia Injury Through Inducing HSP72 in Cerebral Microvascular Endothelial Cells

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