Th17/Treg imbalance modulates rat myocardial fibrosis and heart failure by regulating LOX expression

Lu, Min; Qin, Xinglei; Yao, Jungong; Yang, Yuanyuan; Zhao, Minghu; Sun, Lin

doi:10.1111/apha.13537

Cited by 38 publications

(26 citation statements)

References 24 publications

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“…In addition, IL-23 secreted by Th17 cells can promote the secretion of granulocyte-macrophage colony-stimulating factor by Th17 cells, in ltration of other immune cells, and a chronic in ammatory response (El-Behi et al 2011). An increase in Th17 cells is often accompanied by a decrease in Treg cells (Lu et al 2020), which is consistent with the results observed in this study. Therefore, we propose that VCAM1 promotes HF by regulating Th17 cell in ltration.…”

Section: Discussionsupporting

confidence: 93%

Elevated Myocardial VCAM1 Expression is Associated with Higher Risk of Dilated Cardiomyopathy or Ischemic Heart Disease-caused Heart Failure and Higher Immune Infiltration in Failing Myocardium

Wang

Tian

Jin

2021

Preprint

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Background. Ischemic heart disease (IHD) and dilated cardiomyopathy (DCM) are the two most common etiologies of heart failure (HF). Both forms share common characteristics including ventricle dilation in the final stage. Immune mechanisms in HF are increasingly highlighted and have been implicated in the pathogeneses of IHD and DCM. A better understanding of adhesion molecule expression and correlated immune cell infiltration could enhance disease detection and improve therapeutic targets. Objective. This study was performed to explore the common mechanisms underlying IHD and DCM.Methods. After searching the Gene Expression Omnibus database, we selected the GSE42955 and GS57338 datasets for analysis, which contain 29 and 313 samples, respectively. Results. The screening stage revealed that vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) play pivotal roles in regulating DEGs. Subsequent analyses revealed that VCAM1 was differentially expressed in the myocardium and involved in regulating immune cell infiltration. We also found that dysregulated VCAM1 expression was associated with a higher risk of HF by constructing a clinical risk-predicting model. Conclusions. Collectively, our results suggest that VCAM-1 could be used as a biomarker or therapy target for HF.

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Section: Discussionsupporting

confidence: 93%

Elevated Myocardial VCAM1 Expression is Associated with Higher Risk of Dilated Cardiomyopathy or Ischemic Heart Disease-caused Heart Failure and Higher Immune Infiltration in Failing Myocardium

Wang

Tian

Jin

2021

Preprint

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“… 23 The Th17/Treg imbalance also existed in patients with HFpEF. 24 Decreased Tregs were reported to aggravate myocardial fibrosis and HF, 25 and upregulation of Tregs could ameliorate cardiac dysfunction in chronic heart failure. 25 Our results also show that BHB treatment increased Treg cells and inhibited cardiac inflammation.…”

Section: Discussionmentioning

confidence: 99%

“… 24 Decreased Tregs were reported to aggravate myocardial fibrosis and HF, 25 and upregulation of Tregs could ameliorate cardiac dysfunction in chronic heart failure. 25 Our results also show that BHB treatment increased Treg cells and inhibited cardiac inflammation. These results suggest that BHB not only serves as an energy fuel but also functions as an immunomodulatory agent.…”

Section: Discussionmentioning

confidence: 99%

β-Hydroxybutyrate Mitigated Heart Failure with Preserved Ejection Fraction by Increasing Treg Cells via Nox2/GSK-3β

Liao¹,

Tang²,

Yue³

et al. 2021

JIR

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Background This study was designed to investigate the cardioprotective role of β-hydroxybutyrate (BHB) in heart failure with preserved ejection fraction (HFpEF) and the underlying mechanism. Methods A two-hit model with a high-fat diet (HFD) and N ω -nitrol-arginine methyl ester (L-NAME) was used as an HFpEF model. The treatment group received a weekly intraperitoneal injection of β-hydroxybutyrate (BHB). Cardiac function, inflammation, and fibrosis were evaluated. CD3 + CD4 + Foxp3 + positive cells within the myocardium were quantified by flow cytometry. The NADPH oxidase 2 (NOX2)/glycogen synthase kinase-3β (GSK3β) pathway was examined by immunoblot analysis. Results BHB improved diastolic function, fibrosis and cardiac remodeling in HFpEF. Additionally, BHB inhibited cardiac inflammation and increased cardiac Treg cells, which could be due to the downregulation of the NOX2/GSK-3β pathway. Conclusion BHB protected against the progression of HFpEF by increasing cardiac Treg cells by modulating the NOX2/GSK-3β pathway.

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“…The enzyme lysyl oxidase (LOX) upregulation is associated with vascular fibrosis ( Martinez-Gonzalez et al, 2019 ). A study has shown that Th17 and Treg might modulate LOX expression through their characteristic cytokines IL-17 and IL-10, respectively, thereby regulating fibrosis ( Lu et al, 2020 ). Taken together, the disruption of Treg/Th17 balance and gut microbiota-derived beneficial SCFA reduction are important parameters of the vascular fibrosis in AS.…”

Section: Introductionmentioning

confidence: 99%

Paeonol Attenuated Vascular Fibrosis Through Regulating Treg/Th17 Balance in a Gut Microbiota-Dependent Manner

et al. 2021

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Background: Paeonol (Pae) is a natural phenolic compound isolated from Cortex Moutan, which exhibits anti-atherosclerosis (AS) effects. Our previous work demonstrated that gut microbiota plays an important role during AS treatment as it affects the efficacy of Pae. However, the mechanism of Pae in protecting against vascular fibrosis as related to gut microbiota has yet to be elucidated.Objective: To investigate the antifibrosis effect of Pae on AS mice and demonstrate the underlying gut microbiota-dependent mechanism.Methods: ApoE-/- mice were fed with high-fat diet (HFD) to replicate the AS model. H&E and Masson staining were used to observe the plaque formation and collagen deposition. Short-chain fatty acid (SCFA) production was analyzed through LC-MS/MS. The frequency of immune cells in spleen was phenotyped by flow cytometry. The mRNA expression of aortic inflammatory cytokines was detected by qRT-PCR. The protein expression of LOX and fibrosis-related indicators were examined by western blot.Results: Pae restricted the development of AS and collagen deposition. Notably, the antifibrosis effect of Pae was achieved by regulating the gut microbiota. LC-MS/MS data indicated that the level of SCFAs was increased in caecum contents. Additionally, Pae administration selectively upregulated the frequency of regulatory T (Treg) cells as well as downregulated the ratio of T helper type 17 (Th17) cells in the spleen of AS mice, improving the Treg/Th17 balance. In addition, as expected, Pae intervention can significantly downregulate the levels of proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-17 in the aorta, and upregulate the levels of anti-inflammatory factor IL-10, a marker of Treg cells. Finally, Pae’s intervention in the gut microbiota resulted in the restoration of the balance of Treg/Th17, which indirectly downregulated the protein expression level of LOX and fibrosis-related indicators (MMP-2/9 and collagen I/III).Conclusion: Pae attenuated vascular fibrosis in a gut microbiota-dependent manner. The underlying protective mechanism was associated with the improved Treg/Th17 balance in spleen mediated through the increased microbiota-derived SCFA production. Collectively, our results demonstrated the role of Pae as a potential gut microbiota modulator to prevent and treat AS.

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Th17/Treg imbalance modulates rat myocardial fibrosis and heart failure by regulating LOX expression

Cited by 38 publications

References 24 publications

Elevated Myocardial VCAM1 Expression is Associated with Higher Risk of Dilated Cardiomyopathy or Ischemic Heart Disease-caused Heart Failure and Higher Immune Infiltration in Failing Myocardium

Elevated Myocardial VCAM1 Expression is Associated with Higher Risk of Dilated Cardiomyopathy or Ischemic Heart Disease-caused Heart Failure and Higher Immune Infiltration in Failing Myocardium

β-Hydroxybutyrate Mitigated Heart Failure with Preserved Ejection Fraction by Increasing Treg Cells via Nox2/GSK-3β

Paeonol Attenuated Vascular Fibrosis Through Regulating Treg/Th17 Balance in a Gut Microbiota-Dependent Manner

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