Abstract 501: Hydrogen Sulfide Protects the Heart Against Ferroptotic Cell Death in Diabetic Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sumit Kar ◽  
Hamid Shahshahan ◽  
Paras K Mishra
Keyword(s):  
Cell Death ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Total Protein ◽  
Lipid Peroxide ◽  
Intracellular Iron ◽  
Neonatal Cardiomyocytes ◽  
Primary Neonatal Cardiomyocytes ◽  
And Oxidative Stress

Hyperglycemia-induced death of terminally differentiated cardiomyocytes in diabetic cardiomyopathy (DMCM) leads to heart failure. Ferroptosis is a newly discovered form of cell death triggered by intracellular iron and oxidative stress. While little is known about ferroptosis in DMCM, hyperinsulinemia stimulates intracellular iron uptake, which would be predicted to increase ferroptosis. H 2 S is an endogenous gaseous signaling molecule which may inhibit ferroptosis. H 2 S donors increase glutathione substrate for glutathione peroxidase 4 (GPX4), which removes lipid peroxidation and is the primary inhibitor of ferroptosis. However, no study has investigated the role of H 2 S in ferroptosis. We tested the hypothesis that increased ferroptosis contributes to DMCM, which is ameliorated by restoring H 2 S levels, by measuring ferroptosis in the hearts of db/db mice with DMCM and high glucose treated primary neonatal cardiomyocytes after H 2 S donor treatment. GPX4 expression was decreased (3.21±0.41 GPX4/total protein in db/+ control mice vs. 1.84±0.26 in db/db, P<0.05, n=6/group) and 4-HNE lipid peroxide was increased (7.37±0.98 μg 4-HNE/total protein in db/+ control mice vs. 8.73±0.84 in db/db, P<0.05, n=3/group) in the left ventricle of db/db mice indicating increased ferroptosis in DMCM. GPX4 activity was also decreased along with increased 4-HNE in high glucose cultured cardiomyocytes. Treatment with the ferroptosis inhibitor ferrostatin-1 prevented hyperglycemia induced ferroptosis. Treatment of cardiomyocytes with the H 2 S donor GYY4137 in hyperglycemia also decreased 4-HNE. We also validated the anti-ferroptotic potential of H 2 S by treating cardiomyocytes with the ferroptosis inducer RSL3 and GYY4137. H 2 S donor treatment reduced reactive oxygen species and 4-HNE lipid peroxide seen after ferroptosis induction with RSL3. This study establishes ferroptosis as a new, non-apoptotic, form of cell death in DMCM, and H 2 S as a novel regulator of cardiac ferroptosis.

scholarly journals Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Xinyu Feng ◽  
Shanjie Wang ◽  
Xingjun Yang ◽  
Jie Lin ◽  
Wanrong Man ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Ventricular Remodeling ◽  
Mitochondrial Dynamics ◽  
Left Ventricular Remodeling ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Neonatal Cardiomyocytes ◽  
Primary Neonatal Cardiomyocytes ◽  
Hemodynamic Measurements ◽  
Medium Culture

The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.

Abstract 26: Fibroblast Growth Factor 21 Prevents Diabetic Cardiomyopathy by Attenuating Cardiac Lipotoxicity via Erk1/2-dependent Signaling Pathway in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yi Tan ◽  
Chi Zhang ◽  
Xiaoqing Yan ◽  
Zhifeng Huang ◽  
Junlian Gu ◽  
...  
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Cell ◽  
Diabetic Mice ◽  
Ampk Signaling

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

scholarly journals Hydrogen sulfide-mediated regulation of cell death signaling ameliorates adverse cardiac remodeling and diabetic cardiomyopathy

2019 ◽  
Vol 316 (6) ◽  
pp. H1237-H1252 ◽  
Author(s):  
Sumit Kar ◽  
Tyler N. Kambis ◽  
Paras K. Mishra
Keyword(s):  
Cell Death ◽  
Hydrogen Sulfide ◽  
Diabetic Cardiomyopathy ◽  
Myocardial Cell ◽  
Therapeutic Strategies ◽  
Targeted Therapeutics ◽  
Gaseous Molecule ◽  
Cardioprotective Effects ◽  
Cell Death Signaling ◽  
And Oxidative Stress

The death of cardiomyocytes is a precursor for the cascade of hypertrophic and fibrotic remodeling that leads to cardiomyopathy. In diabetes mellitus (DM), the metabolic environment of hyperglycemia, hyperlipidemia, and oxidative stress causes cardiomyocyte cell death, leading to diabetic cardiomyopathy (DMCM), an independent cause of heart failure. Understanding the roles of the cell death signaling pathways involved in the development of cardiomyopathies is crucial to the discovery of novel targeted therapeutics and biomarkers for DMCM. Recent evidence suggests that hydrogen sulfide (H2S), an endogenous gaseous molecule, has cardioprotective effects against cell death. However, very little is known about signaling by which H2S and its downstream targets regulate myocardial cell death in the DM heart. This review focuses on H2S in the signaling of apoptotic, autophagic, necroptotic, and pyroptotic cell death in DMCM and other cardiomyopathies, abnormalities in H2S synthesis in DM, and potential H2S-based therapeutic strategies to mitigate myocardial cell death to ameliorate DMCM.

Diabetic Cardiomyopathy and Oxidative Stress: Role of Antioxidants

2011 ◽  
Vol 9 (4) ◽  
pp. 225-230 ◽  
Author(s):  
Rajarajan A. Thandavarayan ◽  
Vijayasree V. Giridharan ◽  
Kenichi Watanabe ◽  
Tetsuya Konishi
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
And Oxidative Stress

scholarly journals SIRT3 Is a Stress-Responsive Deacetylase in Cardiomyocytes That Protects Cells from Stress-Mediated Cell Death by Deacetylation of Ku70

2008 ◽  
Vol 28 (20) ◽  
pp. 6384-6401 ◽  
Author(s):  
Nagalingam R. Sundaresan ◽  
Sadhana A. Samant ◽  
Vinodkumar B. Pillai ◽  
Senthilkumar B. Rajamohan ◽  
Mahesh P. Gupta
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Gene Regulation ◽  
Essential Role ◽  
Short Form ◽  
Biological Functions ◽  
Proapoptotic Protein ◽  
Long Form ◽  
And Oxidative Stress

ABSTRACT There are seven SIRT isoforms in mammals, with diverse biological functions including gene regulation, metabolism, and apoptosis. Among them, SIRT3 is the only sirtuin whose increased expression has been shown to correlate with an extended life span in humans. In this study, we examined the role of SIRT3 in murine cardiomyocytes. We found that SIRT3 is a stress-responsive deacetylase and that its increased expression protects myocytes from genotoxic and oxidative stress-mediated cell death. We show that, like human SIRT3, mouse SIRT3 is expressed in two forms, a ∼44-kDa long form and a ∼28-kDa short form. Whereas the long form is localized in the mitochondria, nucleus, and cytoplasm, the short form is localized exclusively in the mitochondria of cardiomyocytes. During stress, SIRT3 levels are increased not only in mitochondria but also in the nuclei of cardiomyocytes. We also identified Ku70 as a new target of SIRT3. SIRT3 physically binds to Ku70 and deacetylates it, and this promotes interaction of Ku70 with the proapoptotic protein Bax. Thus, under stress conditions, increased expression of SIRT3 protects cardiomyocytes, in part by hindering the translocation of Bax to mitochondria. These studies underscore an essential role of SIRT3 in the survival of cardiomyocytes in stress situations.

scholarly journals Evidence that cyclophilin-A protects cells against oxidative stress

1999 ◽  
Vol 341 (1) ◽  
pp. 127-132 ◽  
Author(s):  
Veronica DOYLE ◽  
Sukaina VIRJI ◽  
Martin CROMPTON
Keyword(s):  
Cell Death ◽  
Cyclosporin A ◽  
Cyclophilin A ◽  
Cell Extract ◽  
Protective Role ◽  
Cyclophilin D ◽  
Isomerase Activity ◽  
Neonatal Cardiomyocytes ◽  
Sds Page

Cyclophilin-A is the cytosolic isoform of a family of peptidylproline cis-trans-isomerases that bind cyclosporin A. This study investigates the role of cyclophilin-A in necrotic cell death, induced by ‘chemical ischaemia’ and by t-butylhydroperoxide. An 18-mer antisense phosphorothioate oligodeoxynucleotide was used to target a translated region of cyclophilin-A mRNA in rat neonatal cardiomyocytes. After a 24 h exposure to the oligonucleotide, the amount of cyclophilin-A in the cells was decreased by at least 93% as judged by immunological and enzymic criteria. For the enzyme assays, peptidyl proline cis-trans-isomerase activity was measured fluorimetrically in small (10 μl) volumes of cell extract. Immunoblots were developed with a polyclonal anti-cyclophilin-A antibody after sample isoelectric focusing and SDS/PAGE. Cyclophilin-A suppression had no effect on cyanide-plus-2-deoxyglucose-induced cell death. However, cyclophilin-A-suppressed cells were markedly more sensitive to t-butylhydroperoxide. Cyclosporin A conferred some resistance to the peroxide in both types of cell, but protection was greater in cyclophilin-A-suppressed cells, where cyclosporin A increased the survival time 2-fold. It is concluded that two cyclophilin isoforms are involved, in quite different ways, in peroxide-induced cell death. Cyclophilin-A has a protective role. Another isoform, possibly mitochondrial cyclophilin-D, has a deleterious role, such that blockade by cyclosporin A leads to protection.

scholarly journals SECOND ANOXIA-REOXYGENATION DOES NOT CAUSE THE APOPTOTIC CELL DEATH OF NEONATAL CARDIOMYOCYTES: POSSIBLE ROLE OF CHANGES OF mRNA EXPRESSION OF CYTOPROTECTIVE GENES

2009 ◽  
Vol 55 (1) ◽  
pp. 19-26
Author(s):  
O.V. Surova ◽  
◽  
V.E. Dosenko ◽  
V.S. Nagibin ◽  
L.V. Tumanovskaya ◽  
...  
Keyword(s):  
Cell Death ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Apoptotic Cell ◽  
First Episode ◽  
Mrna Levels ◽  
Neonatal Cardiomyocytes ◽  
Genes Expression ◽  
Shock Proteins

The cells death and genes expression in neonatal cardiomyocytes culture at two anoxia-reoxygenation modeling were investigated. The primary culture of neonatal cardiomyocytes was under­gone 30 min of anoxia followed by 24 h (A-R1) and the second anoxia-reoxygenation – 30 min and 60 min respectively (A-R2). The percentages of living, necrotic, apoptotic and autophagic cells were determined by staining with bis-benzimide, propidium iodide and monodansylcadaverine. Anoxia-reoxygenation sig­nificantly influenced the ratio of living, necrotic, apoptotic and autophagic cells both at its first A-R1 and second A-R2 epi­sodes. It was shown that the main mechanism of cell death after the both periods of anoxia-reoxygenation is necrosis. The changes of mRNA levels of genes of heat shock proteins HSP70 and HSP90, antiapoptotic protein Bcl2 and key regulator of au-tophagy FRAP in cardiomyocytes culture were established. The data obtained allow to make suggestion that in 24 h after the first episode of anoxia-reoxygenation A-R1 the overexpression of heat shock proteins starts the cascade of reactions that causes the necrotic cell death prevalent and the blocking of apoptotic program at second anoxia-reoxygenation A-R2.

scholarly journals The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy

2019 ◽  
Vol 20 (10) ◽  
pp. 2427 ◽  
Author(s):  
Maayan Waldman ◽  
Vadim Nudelman ◽  
Asher Shainberg ◽  
Romy Zemel ◽  
Ran Kornwoski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Beneficial Effect ◽  
Heme Oxygenase ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Heme Oxygenase 1 ◽  
Ros Production ◽  
Diabetic Mice ◽  
Protein Levels

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. Results: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. Conclusion: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.

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