SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Palomer, Xavier; Román-Azcona, M. Silvia; Pizarro-Delgado, Javier; Planavila, Anna; Villarroya, Francesc; Valenzuela-Alcaráz, Brenda; Crispi, F.; Bijnens, Bart; Miguel-Escalada, Irene; Ferrer, Jorge; Nistal, J. Francisco; García, Raquel; Davidson, Mercy M.; Barroso, Emma; Vázquez‐Carrera, Manuel

doi:10.1038/s41392-020-0114-1

Cited by 121 publications

(81 citation statements)

References 46 publications

(74 reference statements)

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“…Consistent with previous studies, inflammation induced by cytokine generation in high‐glucose status resulted in cardiac fibrosis changes and cardiac dysfunctions in DCM (Palomer et al, 2020). We found that the collagen level was increased in experimental diabetic cardiac fibrosis tissue, which was accompanied by reduced LVEF.…”

Section: Discussionsupporting

confidence: 91%

DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis

Tao

Shi

Zhao

et al. 2020

Journal Cellular Physiology

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Cardiac fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Cardiac fibroblast activation is a key effector of cells resulting in diabetic cardiac fibrosis. However, the underlying mechanism of cardiac fibroblast activation and diabetic cardiac fibrosis remains unclear. Accumulating evidence suggests that DNA methylation alterations play a central role in cardiac fibroblast activation. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1)‐mediated suppression of cytokine signaling 3 (SOCS3) promoter hypermethylation leads to downregulation of SOCS3 expression in diabetic cardiac fibrosis. High glucose‐induced expression of DNMT1 was increased in cardiac fibroblasts, while the expression of SOCS3 was decreased. Downregulation of SOCS3 facilitated activation of STAT3 to promote cardiac fibroblast activation and collagen deposition. Genetic or pharmacological inactivation of DNMT1 reversed the activated phenotype of cardiac fibroblasts. Clinically, we observed a significant inverse correlation between DNMT1 and SOCS3 expression levels, and loss of SOCS3 expression or increased expression of DNMT1. Taken together, these findings identify DNMT1 silencing of SOCS3 axis as a driver of cardiac fibroblast activation in diabetic cardiac fibrosis. These results provide a scientific and new explanation of the underlying mechanism of diabetic cardiac fibrosis.

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Section: Discussionsupporting

confidence: 91%

DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis

Tao

Shi

Zhao

et al. 2020

Journal Cellular Physiology

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“…Recent decades, numerous studies have revealed that the mechanism of transcriptional regulation on gene expression were complex, including DNA methylation and transcriptional factors [39][40][41][42]. In present study, we found that the expression of MAPK4 was up-regulated in the lung tissues of ALI mice.…”

Section: Discussionsupporting

confidence: 53%

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4-/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 inhibition using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

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“…Chronic inflammation is another pathological mechanism for CVDs besides oxidative stress [ 24 ]. The cardiac levels of proinflammatory mediators (like IL-6 and TNF-α) are over-generated under pathological stimuli [ 25 ]. D-gal elevates the levels of these inflammatory cytokines in heart [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…D-gal elevates the levels of these inflammatory cytokines in heart [ 26 ]. Furthermore, local inflammation promotes myocyte hypertrophy and interstitial fibrosis, and finally induces cardiac hypertrophy and heart failure [ 25 ]. We found that mangiferin attenuated D-gal-induced cardiac inflammation via decreasing the cardiac levels of IL-1β, IL-6, and TNF-α.…”

Section: Discussionmentioning

confidence: 99%

Mangiferin ameliorates cardiac fibrosis in D-galactose-induced aging rats by inhibiting TGF-β/p38/MK2 signaling pathway

Cheng

Ren

Cheng

et al. 2021

Korean J Physiol Pharmacol

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Aging is the process spontaneously occurred in living organisms. Cardiac fibrosis is a pathophysiological process of cardiac aging. Mangiferin is a well-known C-glucoside xanthone in mango leaves with lots of beneficial properties. In this study, rat model of cardiac fibrosis was induced by injected with 150 mg/kg/d D-galactose for 8 weeks. The age-related cardiac decline was estimated by detecting the relative weight of heart, the serum levels of cardiac injury indicators and the expression of hypertrophic biomakers. Cardiac oxidative stress and local inflammation were measured by detecting the levels of malondialdehyde, enzymatic antioxidant status and proinflammatory cytokines. Cardiac fibrosis was evaluated by observing collagen deposition via masson and sirius red staining, as well as by examining the expression of extracellular matrix proteins via Western blot analysis. The cardiac activity of profibrotic TGF-β1/p38/MK2 signaling pathway was assessed by measuring the expression of TGF-β1 and the phosphorylation levels of p38 and MK2. It was observed that mangiferin ameliorated D-galactose-induced cardiac aging, attenuated cardiac oxidative stress, inflammation and fibrosis, as well as inhibited the activation of TGF-β1/p38/MK2 signaling pathway. These results showed that mangiferin could ameliorate cardiac fibrosis in D-galactose-induced aging rats possibly via inhibiting TGF-β/p38/MK2 signaling pathway.

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SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Cited by 121 publications

References 46 publications

DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis

DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mangiferin ameliorates cardiac fibrosis in D-galactose-induced aging rats by inhibiting TGF-β/p38/MK2 signaling pathway

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