scholarly journals The Opening of ATP-Sensitive K+ Channels Protects H9c2 Cardiac Cells Against the High Glucose-Induced Injury and Inflammation by Inhibiting the ROS-TLR4-Necroptosis Pathway

2017 ◽  
Vol 41 (3) ◽  
pp. 1020-1034 ◽  
Author(s):  
Weijie Liang ◽  
Meiji Chen ◽  
Dongdan Zheng ◽  
Jianhao Li ◽  
Mingcai Song ◽  
...  
Keyword(s):  
Cell Viability ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Katp Channel ◽  
Channel Blocker ◽  
Cardiac Injury ◽  
Cardiac Cells ◽  
Mitochondrial Katp Channel ◽  
Channel Opening ◽  
Pre Treatment

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.

Selective mitochondrial KATP channel opening controls human myocardial preconditioning: Too much of a good thing?

Surgery ◽  
2000 ◽  
Vol 128 (2) ◽  
pp. 368-373 ◽  
Author(s):  
Benjamin J. Pomerantz ◽  
Thomas N. Robinson ◽  
Julie K. Heimbach ◽  
Casey M. Calkins ◽  
Stephanie A. Miller ◽  
...  
Keyword(s):  
Katp Channel ◽  
Good Thing ◽  
Mitochondrial Katp Channel ◽  
Myocardial Preconditioning ◽  
Channel Opening

scholarly journals Fenofibrate Protects Cardiomyocytes from Hypoxia/Reperfusion- and High Glucose-Induced Detrimental Effects

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Fabiola Cortes-Lopez ◽  
Alicia Sanchez-Mendoza ◽  
David Centurion ◽  
Luz G. Cervantes-Perez ◽  
Vicente Castrejon-Tellez ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Glucose ◽  
Cardiac Injury ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Irreversible Damage ◽  
Peroxisome Proliferator Activated Receptor ◽  
Subunit Expression ◽  
Endothelial Nitric Oxide

Lesions caused by high glucose (HG), hypoxia/reperfusion (H/R), and the coexistence of both conditions in cardiomyocytes are linked to an overproduction of reactive oxygen species (ROS), causing irreversible damage to macromolecules in the cardiomyocyte as well as its ultrastructure. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, promotes beneficial activities counteracting cardiac injury. Therefore, the objective of this work was to determine the potential protective effect of fenofibrate in cardiomyocytes exposed to HG, H/R, and HG+H/R. Cardiomyocyte cultures were divided into four main groups: (1) control (CT), (2) HG (25 mM), (3) H/R, and (4) HG+H/R. Our results indicate that cell viability decreases in cardiomyocytes undergoing HG, H/R, and both conditions, while fenofibrate improves cell viability in every case. Fenofibrate also decreases ROS production as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit expression. Regarding the antioxidant defense, superoxide dismutase (SOD Cu2+/Zn2+ and SOD Mn2+), catalase, and the antioxidant capacity were decreased in HG, H/R, and HG+H/R-exposed cardiomyocytes, while fenofibrate increased those parameters. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) increased significantly in treated cells, while pathologies increased the expression of its inhibitor Keap1. Oxidative stress-induced mitochondrial damage was lower in fenofibrate-exposed cardiomyocytes. Endothelial nitric oxide synthase was also favored in cardiomyocytes treated with fenofibrate. Our results suggest that fenofibrate preserves the antioxidant status and the ultrastructure in cardiomyocytes undergoing HG, H/R, and HG+H/R preventing damage to essential macromolecules involved in the proper functioning of the cardiomyocyte.

ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel

2003 ◽  
Vol 284 (1) ◽  
pp. H299-H308 ◽  
Author(s):  
Gilles Lebuffe ◽  
Paul T. Schumacker ◽  
Zuo-Hui Shao ◽  
Travis Anderson ◽  
Hirotoro Iwase ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Methyl Ester ◽  
Katp Channel ◽  
Channel Blocker ◽  
No Synthase ◽  
Oxygen Species ◽  
Channel Activation ◽  
Mitochondrial Katp Channel ◽  
The Relationship

Reactive oxygen species (ROS) and nitric oxide (NO) are implicated in induction of ischemic preconditioning. However, the relationship between these oxidant signals and opening of the mitochondrial ATP-dependent potassium (KATP) channel during early preconditioning is not fully understood. We observed preconditioning protection by hypoxia, exogenous H2O2, or PKC activator PMA in cardiomyocytes subjected to 1-h ischemia and 3-h reperfusion. Protection was abolished by KATP channel blocker 5-hydroxydecanoate (5-HD) in each case, indicating that these triggers must act upstream from the KATP channel. Inhibitors of NO synthase abolished protection in preconditioned cells, suggesting that NO is also required for protection. DAF-2 fluorescence (NO sensitive) increased during hypoxic triggering. This was amplified by pinacidil and inhibited by 5-HD, indicating that NO is generated subsequent to KATP channel activation. Exogenous NO during the triggering phase conferred protection blocked by 5-HD. Exogenous NO also restored protection abolished by 5-HD or N ω-nitro-l-arginine methyl ester in preconditioned cells. Antioxidants given during pinacidil or NO triggering abolished protection, confirming that ROS are generated by KATP channel activation. Coadministration of H2O2 and NO restored PMA-induced protection in 5-HD-treated cells, indicating that ROS and NO are required downstream from the KATP channel. We conclude that ROS can trigger preconditioning by causing activation of the KATP channel, which then induces generation of ROS and NO that are both required for preconditioning protection.

The timing and duration of mitochondrial KATP channel opening determines human myocardial preconditioning

2000 ◽  
Vol 191 (4) ◽  
pp. S35
Author(s):  
Benjamin J Pomerantz ◽  
Anirban Banerjee ◽  
Casey M Calkins ◽  
Julie K Heimbach ◽  
Xianzhong Meng ◽  
...  
Keyword(s):  
Katp Channel ◽  
Mitochondrial Katp Channel ◽  
Myocardial Preconditioning ◽  
Channel Opening

Sequoyitol Alleviates High Glucose-Induced Inflammation, Oxidative Stress and Apoptosis of Retina Epithelial Cells

2021 ◽  
Vol 11 (5) ◽  
pp. 1003-1009
Author(s):  
Liping Hu ◽  
Rui Zhang ◽  
Jianhua Wu ◽  
Chao Feng ◽  
Li Kong
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Cell Viability ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Therapeutic Potential ◽  
Promoting Effect ◽  
Related Factors ◽  
And Oxidative Stress

Diabetic retinopathy (DR) is a serious microvascular complication of diabetes, contributing to visual impairment and blindness. Sequoyitol (Seq), a form of inositol derivatives, has been demonstrated to be a therapeutic potential for diabetes and diabetic nephropathy. The aim of this study is to explore the effects of Seq on DR. ARPE-19 cells were cultured in high glucose (HG) condition to simulate DR in vitro. Seq (1,10 and 20 µM) was applied for treatment. CCK-8 assay was performed to detect cell viability. Flow cytometry analysis was conducted to determine cell apoptosis rate. The production level of inflammatory cytokines and oxidative stress-related factors were determined using their commercial kits. The protein expressions of corresponding genes were detected using western blotting. The results revealed that Seq significantly increased cell viability and protein expression of PCNA and Ki67 which were decreased after HG induction. HG promoted cell apoptosis by decreasing protein expression of Bcl-2 and increasing protein expression of Bax and cleaved caspase-3, which was then reversed by Seq treatment. Besides, Seq abolished the promoting effects of HG on the production of pro-inflammatory cytokines and oxidative stress-related factors. Furthermore, Seq suppressed the promoting effect of HG on the activation of NF-κB signaling by inhibiting phosphorylation of kBa and NF-κB nucleus translocation. These results indicated that Seq might protect ARPE-19 cells against HG-induced cell viability, apoptosis, inflammation and oxidative stress by regulating NF-κB signaling, providing evidence for the potential application of Seq in the therapy of DR.

Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and K+ channel-opening drugs

1995 ◽  
Vol 269 (3) ◽  
pp. C525-C545 ◽  
Author(s):  
A. Terzic ◽  
A. Jahangir ◽  
Y. Kurachi
Keyword(s):  
Katp Channel ◽  
Molecular Mechanisms ◽  
Enzymatic Reaction ◽  
Katp Channels ◽  
Cardiac Cells ◽  
K Channel ◽  
Channel Activity ◽  
Pharmacological Agents ◽  
Channel Opening ◽  
Main Regulator

ATP-sensitive K+ (KATP) channels are present at high density in membranes of cardiac cells where they regulate cardiac function during cellular metabolic impairment. KATP channels have been implicated in the shortening of the action potential duration and the cellular loss of K+ that occurs during metabolic inhibition. KATP channels have been associated with the cardioprotective mechanism of ischemia-related preconditioning. Intracellular ATP (ATPi) is the main regulator of KATP channels. ATPi has two functions: 1) to close the channel (ligand function) and 2) in the presence of Mg2+, to maintain the activity of KATP channels (presumably through an enzymatic reaction). KATP channel activity is modulated by intracellular nucleoside diphosphates that antagonize the ATPi-induced inhibition of channel opening or induce KATP channels to open. How nucleotides will affect KATP channels depends on the state of the channel. K+ channel-opening drugs are pharmacological agents that enhance KATP channel activity through different mechanisms and have great potential in the management of cardiovascular conditions. KATP channel activity is also modulated by neurohormones. Adenosine, through the activation of a GTP-binding protein, antagonizes the ATPi-induced channel closure. Understanding the molecular mechanisms that underlie KATP channel regulation should prove essential to further define the function of KATP channels and to elucidate the pharmacological regulation of this channel protein. Since the molecular structure of the KATP channel has now become available, it is anticipated that major progress in the KATP channel field will be achieved.

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