Hydrogen sulfide alleviates myocardial fibrosis in mice with alcoholic cardiomyopathy by downregulating autophagy

Liang, Biao; Xiao, Ting; Long, Junrong; Liu, Maojun; Li, Zining; Liu, Shengquan; Yang, Jun

doi:10.3892/ijmm.2017.3191

Cited by 23 publications

(23 citation statements)

References 61 publications

(57 reference statements)

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“…Changes in H 2 S were not due to changes in homocysteine, a non-protein coding amino acid which is a precursor of H 2 S and can be altered by diet [43]. Several mechanisms have been demonstrated for how H 2 S protects against cell death, including by the reduction of inflammatory cytokines such as IL-1β [44], stimulating antioxidant production [45], and downregulating autophagy [46].…”

Section: Discussionmentioning

confidence: 99%

Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

et al. 2019

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Obesity increases the risk of developing diabetes and subsequently, diabetic cardiomyopathy (DMCM). Reduced cardioprotective antioxidant hydrogen sulfide (H 2 S) and increased inflammatory cell death via pyroptosis contribute to adverse cardiac remodeling and DMCM. Although exercise training (EX) has cardioprotective effects, it is unclear whether EX mitigates obesity-induced DMCM by increasing H 2 S biosynthesis and mitigating pyroptosis in the heart. C57BL6 mice were fed a high-fat diet (HFD) while undergoing treadmill EX for 20 weeks. HFD mice developed obesity, hyperglycemia, and insulin resistance, which were reduced by EX. Left ventricle pressure-volume measurement revealed that obese mice developed reduced diastolic function with preserved ejection fraction, which was improved by EX. Cardiac dysfunction was accompanied by increased cardiac pyroptosis signaling, structural remodeling, and metabolic remodeling, indicated by accumulation of lipid droplets in the heart. Notably, EX increased cardiac H 2 S concentration and expression of H 2 S biosynthesis enzymes. HFD-induced obesity led to features of type 2 diabetes (T2DM), and subsequently DMCM. EX during the HFD regimen prevented the development of DMCM, possibly by promoting H 2 S-mediated cardioprotection and alleviating pyroptosis. This is the first report of EX modulating H 2 S and pyroptotic signaling in the heart. mechanisms induced by EX to ameliorate cardiac dysfunction would lead to novel therapeutic targets for DMCM-especially in patients unable to exercise.Cardiomyocyte cell death is a key molecular event in the progression of DMCM, as the death of terminally differentiated cardiomyocytes leads to loss of contractile units and instigates fibrosis [12]. In metabolic syndrome, the diabetic environment of hyperglycemia, inflammatory cytokines, oxidative damage, and lipotoxicity induces several types of cell death, including non-inflammatory (apoptosis), and inflammatory (pyroptosis) cell death in the heart [13][14][15]. Pyroptosis is an inflammasome-mediated cell death mechanism where activation of the NOD-like receptor protein 3 (NLRP3) inflammasome activates caspase-1 and results in cell lysis and release of the interleukin IL-1β [16]. Hyperglycemia, fatty acids, and oxidative stress activate NLRP3 and caspase-1-mediated inflammasome, and inhibition of NLRP3 mitigates DMCM in diabetic rats [17][18][19]. Furthermore, HFD and obesity lead to inflammasome activation and infiltration of macrophages into adipose tissue, the key player in pyroptosis [18,20]. However, the role of pyroptosis in obesity-induced cardiac remodeling is unclear. Vandanmagsar et al. demonstrated that EX reduces pyroptotic cell death in adipose and liver tissue, however, this effect has not been evaluated in the heart [18].Hydrogen sulfide (H 2 S), a cardioprotective gaseous signaling molecule produced by homocysteine transsulfuration, prevents adverse cardiac remodeling and cell death, including pyroptosis [21]. H 2 S inhibits caspase-1 activity and IL-1β secretion both in vit...

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Section: Discussionmentioning

confidence: 99%

Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

et al. 2019

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“…The irreversible and progressive pulmonary fibrosis leading to respiratory function failure is still the main cause of PQ‐induced death (Dinis‐Oliveira et al, ). Recently, increasing evidence indicates that plasma H 2 S is low level in several animal models of fibrotic diseases and a supplement of exogenous H 2 S is able to ameliorate fibrosis in the kidney (Han et al, ; L. Li et al, ; Li, Li, Zeng, Liu, & Yang, ), heart (Li et al, ; Liang et al, ; Liu et al, ), liver (Mani, Cao, Wu, & Wang, ), peritoneum (Lu et al, ), skin and lung (Fang et al, ; Wang et al, ). As a significant process towards fibrogenesis, EMT characterizes the morphological changes associated with the downregulation of epithelial cell markers, such as E‐cadherin, and upregulation of mesenchymal markers, such as vimentin (Cannito et al, ).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide attenuates paraquat‐induced epithelial‐mesenchymal transition of human alveolar epithelial cells through regulating transforming growth factor‐β1/Smad2/3 signaling pathway

Bai

Yang

et al. 2018

J of Applied Toxicology

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Exogenous H2S donor, sodium hydrosulfide (NaHS), can influence the bleomycin‐induced pulmonary fibrosis by attenuating the epithelial‐mesenchymal transition (EMT) of alveolar epithelial cells, but whether NaHS affects paraquat (PQ)‐induced EMT and the molecular mechanisms remain unclarified. The aim of the present study is to examine the effect of exogenous NaHS on PQ‐induced EMT in human alveolar epithelial cells (A549 cells) and assess if this effect occurs through regulating transforming growth factor (TGF)‐β1/Smad2/3 signaling pathway. The expressions of endogenous H2S producing enzymes, namely cystathionine β‐synthase, cystathionine γ‐lyase and 3‐mercaptopyruvate sulfur transferase, were detected by reverse transcription‐polymerase chain reaction and western blotting. The induced EMT was assessed by morphological and phenotypic characterizations, and the protein level of E‐cadherin and vimentin were detected by western blotting. To investigate the effect of NaHS on PQ‐induced EMT and potential mechanism, A549 cells were pretreated with NaHS before incubating with PQ and then evaluated by morphological changes, cell migration ability, the expression of EMT markers and TGF‐β1/Smad2/3 signaling pathway related proteins. PQ significantly downregulated the expression levels of cystathionine β‐synthase and cystathionine γ‐lyase, but not 3‐mercaptopyruvate sulfur transferase, in a time‐dependent manner in A549 cells. Exogenous NaHS could significantly retard PQ‐induced morphological changes and cell migration ability. Furthermore, exogenous NaHS significantly upregulated the expression of E‐cadherin, whereas it downregulated the expression of vimentin. In addition, exogenous NaHS could also significantly attenuates PQ‐induced TGF‐β1, phosphorylated Smad2/3 proteins expression, which induced by PQ in a time‐dependent manner. This study provides the first evidence that exogenous NaHS attenuates PQ‐induced EMT and migration of human alveolar epithelial cells through regulating the TGF‐β1/Smad2/3 signaling pathway.

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“…In diabetic rats, H 2 S donor NaHS inhibited the expression of MMP14 in myocardial tissues through JAK/STAT signaling pathway [25]. In alcoholic cardiomyopathy mice, H 2 S donor NaHS inhibited the expression of MMP14 in myocardial tissues through miR-21 and miR-211 [26]. However, whether JAK/STAT signaling pathway, miRs pathway are involved in modulation effect of H 2 S on the expression of MMP14 need further investigation.…”

Section: Discussionmentioning

confidence: 98%

Reduced cystathionine-γ-lyase (CSE) expression is involved in high glucose induced MMP14 expression in adipocytes and adipose tissues

Hu¹,

Si²,

Ruan³

et al. 2019

Endocr J

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In the present study, we investigate the effect of reduced cystathionine-γ-lyase (CSE) expression in high glucose induced metalloproteinases14 (MMP14) expression in adipocytes and visceral adipose tissues. Diabetic mice were prepared by injections of STZ and the expression of CSE, MMP14 in visceral adipose tissues were determined. Adipocytes were differentiated from 3T3-L1 cells and treated with high glucose (HG), H 2 S slow-releasing compound GYY4137 or transfected with CSE siRNA. Then the expression of CSE, MMP14 were determined by western blotting. CSE knockout mice were generated by crossing CSE +/heterozygous mice and given intraperitoneally (i.p.) injections of GYY4137, and then the expression of CSE and MMP14 in visceral adipose tissues were determined by quantitative real-time PCR and western blotting. The following results were obtained from the study. In adipose tissues of diabetic mice, the mRNA and protein expression of MMP14 increased while the mRNA and protein expression of CSE decreased. In 3T3-L1 adipocytes, both HG DMEM and CSE siRNA transfection increased the mRNA and protein of MMP14. The addition of GYY4137 inhibited HGinduced upregulation of MMP14 expression. In CSE knockout mice, the mRNA and protein expression of MMP14 in adipose tissues increased, which could be inhibited by i.p. injections of GYY4137. In conclusion, high glucose increased the expression of MMP14 in adipocytes and visceral adipose tissues through inhibiting the expression of CSE.

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Hydrogen sulfide alleviates myocardial fibrosis in mice with alcoholic cardiomyopathy by downregulating autophagy

Cited by 23 publications

References 61 publications

Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

Hydrogen sulfide attenuates paraquat‐induced epithelial‐mesenchymal transition of human alveolar epithelial cells through regulating transforming growth factor‐β1/Smad2/3 signaling pathway

Reduced cystathionine-γ-lyase (CSE) expression is involved in high glucose induced MMP14 expression in adipocytes and adipose tissues

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