06 AT1A receptor blockade by L-158,809 prevents the development of high [glucose]-induced diabetic cardiomyopathy: Role of NADPH oxidase

Abstract Background Diabetic cardiomyopathy is a main cause of the increased morbidity in diabetic patients, no effective treatment is available so far. Polydatin, a resveratrol glucoside isolated from the Polygonum cuspidatum, was found by our and others have antioxidant and cardioprotective activities. Therapeutic effects of polydatin on diabetic cardiomyopathy and the possible mechanisms remains unclear. This study aimed to investigate the cardioprotective effects and underlying mechanisms of polydatin on myocardial injury induced by hyperglycemia. Methods Diabetes in rats was made by high-fat diet combined with multiple low doses of streptozotocin, and then treated with polydatin (100 mg·kg-1·day-1, by gavage) for 8 weeks. Cardiac function was examined by echocardiography. Myocardial tissue and blood samples were collected for histology, protein and metabolic characteristics analysis. In cultured H9c2 cells with 30 mM of glucose, the direct effects of polydatin on myocyte injury were also observed. Results In diabetic rats, polydatin administration significantly improved myocardial dysfunction and attenuated histological abnormalities, as evidenced by elevating left ventricular shortening fraction and ejection fraction, as well as reducing cardiac hypertrophy and interstitial fibrosis. In cultured H9c2 cells, pretreatment of polydatin dose-dependently inhibited high glucose-induced cardiomyocyte injury. Further observation evidenced that polydatin suppressed the increase in the reactive oxygen species levels, NADPH oxidase activity and inflammatory cytokines production induced by hyperglycemia in vivo and in vitro. Polydatin also prevented the increase expression of NOX4, NOX2 and NF-κB in the high glucose -stimulated H9c2 cells and diabetic hearts. Conclusions Our results demonstrate that the cardioprotective effect of polydatin against hyperglycemia-induced myocardial injury is mediated by inhibition of NADPH oxidase and NF-κB activity. The findings may provide a novel understanding the mechanisms of the polydatin to be a potential treatment of diabetic cardiomyopathy.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20102427 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2427 ◽

Cited By ~ 8

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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Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21207432 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7432 ◽

Cited By ~ 1

Author(s):

Micaela Gliozzi ◽

Federica Scarano ◽

Vincenzo Musolino ◽

Cristina Carresi ◽

Miriam Scicchitano ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Nadph Oxidase ◽

Diabetic Cardiomyopathy ◽

Superoxide Anion ◽

Matrix Metalloproteinase 2 ◽

Superoxide Anion Production ◽

Anion Production ◽

Voltage Dependent ◽

Selective Channel

Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX™ staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a “frail” myocardial tissue unable to adapt itself to stress.

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

Circulation Research ◽

10.1161/res.127.suppl_1.501 ◽

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.

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Abstract: P226 STUDY OF HIGH GLUCOSE-INDUCED APOPTOSIS IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS: ROLE OF NADPH OXIDASE 4 GENE

Atherosclerosis Supplements ◽

10.1016/s1567-5688(09)70533-1 ◽

2009 ◽

Vol 10 (2) ◽

pp. e545

Author(s):

D Feng ◽

W Fan ◽

F Guo ◽

C Zhang ◽

S Qu

Keyword(s):

Endothelial Cells ◽

Nadph Oxidase ◽

High Glucose ◽

Umbilical Vein ◽

Human Umbilical Vein ◽

Nadph Oxidase 4 ◽

Induced Apoptosis ◽

Umbilical Vein Endothelial Cells

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A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

Frontiers in Pharmacology ◽

10.3389/fphar.2021.708177 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu-jie Xing ◽

Biao-hu Liu ◽

Shu-jun Wan ◽

Yi Cheng ◽

Si-min Zhou ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Diabetic Cardiomyopathy ◽

High Glucose ◽

Sglt2 Inhibitor ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

H9c2 Cells ◽

Myocardial Oxidative Stress

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress.

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