Chemical communication between cardiac cells is disrupted by high glucose: Implications for the diabetic heart

Background/Aims: Hyperglycemia activates multiple signaling molecules, including reactive oxygen species (ROS), toll-like receptor 4 (TLR4), receptor-interacting protein 3 (RIP3, a kinase promoting necroptosis), which mediate hyperglycemia-induced cardiac injury. This study explored whether inhibition of ROS-TLR4-necroptosis pathway contributed to the protection of ATP-sensitive K+ (KATP) channel opening against high glucose-induced cardiac injury and inflammation. Methods: H9c2 cardiac cells were treated with 35 mM glucose (HG) to establish a model of HG-induced insults. The expression of RIP3 and TLR4 were tested by western blot. Generation of ROS, cell viability, mitochondrial membrane potential (MMP) and secretion of inflammatory cytokines were measured as injury indexes. Results: HG increased the expression of TLR4 and RIP3. Necrostatin-1 (Nec-1, an inhibitor of necroptosis) or TAK-242 (an inhibitor of TLR4) co-treatment attenuated HG-induced up-regulation of RIP3. Diazoxide (DZ, a mitochondrial KATP channel opener) or pinacidil (Pin, a non-selective KATP channel opener) or N-acetyl-L-cysteine (NAC, a ROS scavenger) pre-treatment blocked the up-regulation of TLR4 and RIP3. Furthermore, pre-treatment with DZ or Pin or NAC, or co-treatment with TAK-242 or Nec-1 attenuated HG-induced a decrease in cell viability, and increases in ROS generation, MMP loss and inflammatory cytokines secretion. However, 5-hydroxy decanoic acid (5-HD, a mitochondrial KATP channel blocker) or glibenclamide (Gli, a non-selective KATP channel blocker) pre-treatment did not aggravate HG-induced injury and inflammation. Conclusion: KATP channel opening protects H9c2 cells against HG-induced injury and inflammation by inhibiting ROS-TLR4-necroptosis pathway.

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Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

International Journal of Molecular Medicine ◽

10.3892/ijmm.2013.1462 ◽

2013 ◽

Vol 32 (4) ◽

pp. 917-925 ◽

Cited By ~ 37

Author(s):

WENMING XU ◽

WEN WU ◽

JINGFU CHEN ◽

RUNMIN GUO ◽

JIANCONG LIN ◽

...

Keyword(s):

Hydrogen Sulfide ◽

P38 Mapk ◽

High Glucose ◽

Cardiac Cells

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Inactivation of TOPK Caused by Hyperglycemia Blocks Diabetic Heart Sensitivity to Sevoflurane Postconditioning by Impairing the PTEN/PI3K/Akt Signaling

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6657529 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Sumin Gao ◽

Rong Wang ◽

Siwei Dong ◽

Jing Wu ◽

Bartłomiej Perek ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Kinase ◽

High Glucose ◽

Ischemia Reperfusion ◽

Akt Signaling ◽

Cardioprotective Effect ◽

Diabetic Heart ◽

H9c2 Cells ◽

Sevoflurane Postconditioning ◽

And Oxidative Stress

The cardioprotective effect of sevoflurane postconditioning (SPostC) is lost in diabetes that is associated with cardiac phosphatase and tensin homologue on chromosome 10 (PTEN) activation and phosphoinositide 3-kinase (PI3K)/Akt inactivation. T-LAK cell-originated protein kinase (TOPK), a mitogen-activated protein kinase- (MAPKK-) like serine/threonine kinase, has been shown to inactivate PTEN (phosphorylated status), which in turn activates the PI3K/Akt signaling (phosphorylated status). However, the functions of TOPK and molecular mechanism underlying SPostC cardioprotection in nondiabetes but not in diabetes remain unknown. We presumed that SPostC exerts cardioprotective effects by activating PTEN/PI3K/Akt through TOPK in nondiabetes and that impairment of TOPK/PTEN/Akt blocks diabetic heart sensitivity to SPostC. We found that in the nondiabetic C57BL/6 mice, SPostC significantly attenuated postischemic infarct size, oxidative stress, and myocardial apoptosis that was accompanied with enhanced p-TOPK, p-PTEN, and p-Akt. These beneficial effects of SPostC were abolished by either TOPK kinase inhibitor HI-TOPK-032 or PI3K/Akt inhibitor LY294002. Similarly, SPostC remarkably attenuated hypoxia/reoxygenation-induced cardiomyocyte damage and oxidative stress accompanied with increased p-TOPK, p-PTEN, and p-Akt in H9c2 cells exposed to normal glucose, which were canceled by either TOPK inhibition or Akt inhibition. However, either in streptozotocin-induced diabetic mice or in H9c2 cells exposed to high glucose, the cardioprotective effect of SPostC was canceled, accompanied by increased oxidative stress, decreased TOPK phosphorylation, and impaired PTEN/PI3K/Akt signaling. In addition, TOPK overexpression restored posthypoxic p-PTEN and p-Akt and decreased cell death and oxidative stress in H9c2 cells exposed to high glucose, which was blocked by PI3K/Akt inhibition. In summary, SPostC prevented myocardial ischemia/reperfusion injury possibly through TOPK-mediated PTEN/PI3K/Akt activation and impaired activation of this signaling pathway may be responsible for the loss of SPostC cardioprotection by SPostC in diabetes.

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ALDH2 Overexpression Alleviates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation

Journal of Diabetes Research ◽

10.1155/2019/4857921 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Ruiping Cao ◽

Dian Fang ◽

Jiahui Wang ◽

Ying Yu ◽

Hongwei Ye ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

High Glucose ◽

Myocardial Injury ◽

Cell Injury ◽

Cardiac Cells ◽

Receptor Protein ◽

Inflammasome Activation ◽

Ros Production ◽

Cardiac Cell ◽

Inflammation Reaction

Although the underlying mechanisms of diabetes-induced myocardial injury have not been fully illuminated, the inflammation reaction has been reported intently linked with diabetes. The nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, the key component of pyroptosis, is involved in inflammation reaction, which may be one of the important mechanisms in diabetes-induced myocardial injury. The purpose of this study was to investigate the changes of NLRP3 inflammasome and pyroptosis in high glucose-induced H9C2 cardiac cell injury and investigate whether overexpression of mitochondrial aldehyde dehydrogenase 2 (ALDH2) can reduce the occurrence of pyroptosis. The H9C2 cardiac cells were exposed to 35 mM glucose for 24 h to induce cytotoxicity. Mitochondrial ALDH2 overexpression cardiac cell line was constructed. The results showed in high glucose condition that ALDH2 overexpression significantly increased H9C2 cardiac cell viability, increased mitochondrial ALDH2 activity and protein expression, and reduced mitochondrial reactive oxygen species (ROS) production, 4-hydroxynonenal (4-HNE), and lactate dehydrogenase (LDH) levels; meanwhile, the pyroptosis key components—NLRP3 inflammasome-related proteins, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cysteine-containing aspartate specific protease 1 (Caspase-1), and interleukin-18 (IL-18) protein expressions—were significantly decreased, and IL-18 and interleukin-1β (IL-1β) levels were also decreased. In high glucose-induced cardiac cell injury, ALDH2 overexpression may reduce ROS production, thereby inhibiting the activation of NLRP3 inflammation and cell pyroptosis. ALDH2 gene might play the potential role in the treatment of high glucose-induced H9C2 cardiac cell injury.

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Bis(maltolato)oxovanadium(IV) (BMOV) Attenuates Apoptosis in High Glucose-Treated Cardiac Cells and Diabetic Rat Hearts by Regulating the Unfolded Protein Responses (UPRs)

Biological Trace Element Research ◽

10.1007/s12011-016-0668-5 ◽

2016 ◽

Vol 173 (2) ◽

pp. 390-398 ◽

Cited By ~ 14

Author(s):

Xiao-Qiang Cong ◽

Mei-Hua Piao ◽

Ying Li ◽

Lin Xie ◽

Ya Liu

Keyword(s):

High Glucose ◽

Cardiac Cells ◽

Diabetic Rat ◽

Unfolded Protein Responses ◽

Unfolded Protein ◽

Rat Hearts

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Exogenous hydrogen sulfide protects against high glucose-induced inflammation and cytotoxicity in H9c2 cardiac cells

Molecular Medicine Reports ◽

10.3892/mmr.2016.5846 ◽

2016 ◽

Vol 14 (5) ◽

pp. 4911-4917 ◽

Cited By ~ 5

Author(s):

Zena Huang ◽

Xiaobian Dong ◽

Xiaodong Zhuang ◽

Xun Hu ◽

Lichun Wang ◽

...

Keyword(s):

Hydrogen Sulfide ◽

High Glucose ◽

Cardiac Cells

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IGFBP5 mediates high glucose-induced cardiac fibroblast activation

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0194 ◽

2013 ◽

Vol 50 (3) ◽

pp. 291-303 ◽

Cited By ~ 19

Author(s):

Seung Eun Song ◽

Yong-Woon Kim ◽

Jong-Yeon Kim ◽

Dong Hyup Lee ◽

Jae-Ryong Kim ◽

...

Keyword(s):

Cell Proliferation ◽

High Glucose ◽

Cardiac Fibroblasts ◽

Diabetic Rats ◽

Cardiac Cells ◽

Matrix Metalloproteinase 2 ◽

Mrna Levels ◽

Sprague Dawley ◽

Protein Levels ◽

Collagen Iii

This study examined whether IGF-binding protein 5 (IGFBP5) is involved in the high glucose-induced deteriorating effects in cardiac cells. Cardiac fibroblasts and cardiomyocytes were isolated from the hearts of 1- to 3-day-old Sprague Dawley rats. Treatment of fibroblasts with 25 mM glucose increased the number of cells and the mRNA levels of collagen III, matrix metalloproteinase 2 (MMP2), andMMP9. High glucose increased ERK1/2 activity, and the ERK1/2 inhibitor PD98059 suppressed high glucose-mediated fibroblast proliferation and increased collagen III mRNA levels. Whereas high glucose increased both mRNA and protein levels of IGFBP5 in fibroblasts, high glucose did not affect IGFBP5 protein levels in cardiomyocytes. The high glucose-induced increase in IGFBP5 protein levels was inhibited by PD98059 in fibroblasts. While recombinant IGFBP5 increased ERK phosphorylation, cell proliferation, and the mRNA levels of collagen III,MMP2, andMMP9in fibroblasts, IGFBP5 increased c-Jun N-terminal kinase phosphorylation and induced apoptosis in cardiomyocytes. The knockdown of IGFBP5 inhibited high glucose-induced cell proliferation and collagen III mRNA levels in fibroblasts. Although high glucose increased IGF1 levels, IGF1 did not increase IGFBP5 levels in fibroblasts. The hearts of Otsuka Long-Evans Tokushima Fatty rats and the cardiac fibroblasts of streptozotocin-induced diabetic rats showed increased IGFBP5 expression. These results suggest that IGFBP5 mediates high glucose-induced profibrotic effects in cardiac fibroblasts.

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