Oxidized phosphatidylcholines trigger ferroptosis in cardiomyocytes during ischemia/reperfusion injury

2021 ◽  
Author(s):  
Aleksandra Stamenkovic ◽  
Kimberley A. O'Hara ◽  
David C. Nelson ◽  
Thane G Maddaford ◽  
Andrea L. Edel ◽  
...  
Keyword(s):  
Cell Death ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Calcium Transients ◽  
Tunel Staining ◽  
Dependent Manner ◽  
Mediate Cell ◽  
Myocardial Ischemia Reperfusion ◽  
Vehicle Treated Control

Myocardial ischemia/reperfusion (I/R) injury increases the generation of oxidized phosphatidylcholines (OxPCs) which results in cell death. However, the mechanism by which OxPCs mediate cell death is largely unknown. The aim of this study was to determine the mechanisms by which OxPC triggers cardiomyocyte cell death during reperfusion injury. Cardiomyocyte viability, bioenergetic response and calcium transients were determined in the presence of OxPCs. Fragmented OxPCs resulted in a decrease in cell viability with POVPC and PONPC having the most potent cardiotoxic effect in both a concentration and time dependent manner (P<0.05). POVPC and PONPC also caused a significant decrease in Ca2+ transients and net contraction in isolated cardiomyocytes compared to vehicle treated control cells (P<0.05). PONPC depressed maximal respiration rate (p<0.01; 54%) and spare respiratory capacity (p<0.01; 54.5%). Notably, neither caspase 3 activation or TUNEL staining was observed in cells treated with either POVPC or PONPC. Further, cardiac myocytes treated with OxPCs were indistinguishable from vehicle treated control cells with respect to nuclear HMGB1 activity. Glutathione peroxidase 4 activity was markedly suppressed in cardiomyocytes treated with POVPC and PONPC. Importantly, cell death induced by OxPCs could be suppressed E06 Ab, directed against OxPCs or by ferrostatin. The findings of the present study suggest that OxPCs disrupt mitochondrial bioenergetics, calcium transients and provoke wide spread cell death through ferroptosis during I/R. Neutralization of OxPC with E06 or with ferrostatin-1 prevents cell death during reperfusion. Our study demonstrates a novel signaling pathway that operationally links generation of OxPC during cardiac I/R to ferroptosis.

scholarly journals AMPK/SIRT1 Pathway is Involved in Arctigenin-Mediated Protective Effects Against Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Vol 11 ◽  
Author(s):  
Cheng-Yin Liu ◽  
Yi Zhou ◽  
Tao Chen ◽  
Jing-Chao Lei ◽  
Xue-Jun Jiang
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Arctigenin, one of the active ingredients extracted from Great Burdock (Arctium lappa) Achene, has been found to relieve myocardial infarction injury. However, the specific mechanism of Arctigenin against myocardial infarction remains largely unknown. Here, both acute myocardial ischemia-reperfusion injury (AMI/R) rat model and oxygen glucose deprivation (OGD)-induced myocardial cell injury model were constructed to explore the underlying role of AMPK/SIRT1 pathway in Arctigenin-mediated effects. The experimental data in our study demonstrated that Arctigenin ameliorated OGD-mediated cardiomyocytes apoptosis, inflammation and oxidative stress in a dose-dependent manner. Besides, Arctigenin activated AMPK/SIRT1 pathway and downregulated NF-κB phosphorylation in OGD-treated cardiomyocytes, while inhibiting AMPK or SIRT1 by the Compound C (an AMPK inhibitor) or SIRT1-IN-1 (a SIRT1 inhibitor) significantly attenuated Arctigenin-exerted protective effects on cardiomyocytes. In the animal experiments, Arctigenin improved the heart functions and decreased infarct size of the AMI/R-rats, accompanied with downregulated oxidative stress, inflammation and apoptotic levels in the heart tissues. What’s more, Arctigenin enhanced the AMPK/SIRT1 pathway and repressed NF-κB pathway activation. Taken together, our data indicated that Arctigenin reduced cardiomyocytes apoptosis against AMI/R-induced oxidative stress and inflammation at least via AMPK/SIRT1 pathway.

scholarly journals Evaluation of Biological Activity Exerted by an Aza-bicyclocarboxylic acid Derivative using Anischemia-Reperfusion Injury Model

2018 ◽  
Vol 11 (4) ◽  
pp. 1865-1877
Author(s):  
Figueroa-Valverde Lauro ◽  
Rosas-Nexticapa Marcela ◽  
Mateu-Armand Virginia ◽  
Herrera-Meza Socorro ◽  
Díaz-Cedillo Francisco ◽  
...  
Keyword(s):  
Biological Activity ◽  
Carboxylic Acid ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Camp Levels

The main objective of this study was to evaluate the biological activity of a new compound (derived from aza-bicyclo-carboxylic acid) against heart failure caused by the ischemia- reperfusion phenomenon. In addition, to characterize de molecular mechanism involved in the effect exerted by aza-bicyclo-carboxylic acid against infarction area, some drugs such as prazosin, metoprolol, propanolol, tamoxifen, flutamide, finasteride, nifedipine, levosimedan, adenosine, rolofylline, isoproterenol and the compound ZM-241385 were used as pharmacological tools. The data found indicated that biological activity induced by compound 3 on infarction area only was similar at effect exerted by adenosine; however, the effect produced by compound 3 was blocked with of rolofylline. Other data showed that the biological activity of compound 3 decreases the cAMP levels in a time-dependent manner. In conclusion, the results indicate that compound 3 can produce a cardioprotective effect against myocardial ischemia-reperfusion injury translated as a decrease on infarction area; this phenomenon involves A1-adenosine receptor activation and, as a result may cause changes in cAMP levels.

scholarly journals Visnagin ameliorates myocardial ischemia/reperfusion injury through the promotion of autophagy and the inhibition of apoptosis

2020 ◽  
Vol 64 (s2) ◽  
Author(s):  
Hai-rong Fu ◽  
Xiao-shan Li ◽  
Yong-hui Zhang ◽  
Bin-bin Feng ◽  
Lian-hong Pan
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tunel Staining ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Visnagin is a furanochromone and one of the main compounds of Ammi visnaga L. that had been used to treat nephrolithiasis in Ancient Egypt. Nowadays, visnagin was widely used to treat angina pectoris, urolithiasis and hypertriglyceridemia. The potential mechanisms of visnagin involved in inflammation and cardiovascular disease were also identified. But the protective effect of visnagin on myocardial ischemia/reperfusion injury has not been confirmed. Our aim was, for the first time, to investigate the potential protective effect of visnagin on cardiac function after myocardial ischemia-reperfusion injury in a rat model, and to identify its underlying mechanism involving the inhibition of apoptosis and induction of autophagy. Thirty SD rats were randomly divided into sham group, ischemia/reperfusion group (IR), ischemia/reperfusion with visnagin (IR + visnagin) group. Myocardial ischemia/Reperfusion injury model was established. Hemodynamic measurements and echocardiography were used to analyze cardiac function, TUNEL staining and caspase activity, LC3 dots were detected with immunofluorescence staining, LC3 expression was evaluated by western blot analysis, transmission electron microscopy (TEM) was used to detect autophagosomes. Compared with the sham group and visnagin group, the cardiac dysfunction, LC3II, autophagy flow in the IR+ visnagin group increased significantly (P<0.01), but the activity of caspase-3 and caspase-9 and the apoptotic in the IR + visnagin group decreased significantly (P<0.01). In conclusion, visnagin may play a protective role in ischemia/reperfusion injury by inducing autophagy and reducing apoptosis.

scholarly journals Enhancing Glycolysis Protects against Ischemia-Reperfusion Injury by Reducing ROS Production

Metabolites ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 132
Author(s):  
Claudia Beltran ◽  
Rosario Pardo ◽  
Diana Bou-Teen ◽  
Marisol Ruiz-Meana ◽  
Josep A. Villena ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Glucose Oxidation ◽  
Ischemia Reperfusion Injury ◽  
Aerobic Glycolysis ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Metabolic Shift ◽  
Myocardial Ischemia Reperfusion

After myocardial ischemia-reperfusion, fatty acid oxidation shows fast recovery while glucose oxidation rates remain depressed. A metabolic shift aimed at increasing glucose oxidation has shown to be beneficial in models of myocardial ischemia-reperfusion. However, strategies aimed at increasing glucose consumption in the clinic have provided mixed results and have not yet reached routine clinical practice. A better understanding of the mechanisms underlying the protection afforded by increased glucose oxidation may facilitate the transfer to the clinic. The purpose of this study was to evaluate if the modulation of reactive oxygen species (ROS) was involved in the protection afforded by increased glucose oxidation. Firstly, we characterized an H9C2 cellular model in which the use of glucose or galactose as substrates can modulate glycolysis and oxidative phosphorylation pathways. In this model, there were no differences in morphology, cell number, or ATP and PCr levels. However, galactose-grown cells consumed more oxygen and had an increased Krebs cycle turnover, while cells grown in glucose had increased aerobic glycolysis rate as demonstrated by higher lactate and alanine production. Increased aerobic glycolysis was associated with reduced ROS levels and protected the cells against simulated ischemia-reperfusion injury. Furthermore, ROS scavenger N-acetyl cysteine (NAC) was able to reduce the amount of ROS and to prevent cell death. Lastly, cells grown in galactose showed higher activation of mTOR/Akt signaling pathways. In conclusion, our results provide evidence indicating that metabolic shift towards increased glycolysis reduces mitochondrial ROS production and prevents cell death during ischemia-reperfusion injury.

Mechanisms of Paeoniflorin against myocardial ischemia reperfusion injury based on network pharmacology

2021 ◽  
Vol 11 (9) ◽  
pp. 1505-1515
Author(s):  
Chengguo Zhao ◽  
Meifang Yin ◽  
Feng Li ◽  
Wenpei Ling ◽  
Chunyu Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Network Pharmacology ◽  
Tunel Staining ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Myocardial Enzymes

Ischemic heart disease (IHD) is the primary reason of death of cardiovascular diseases. Paeoniflorin (PF), a monoterpene glycoside extracted from Radix Paeoniae Rubra or Paeoniae Radix Alba, can ameliorate myocardial ischemia/reperfusion injury (MIRI), but its mechanism is not still defined. In this study, network pharmacology was utilized, the protein interaction network between PF and MIRI targets were screened for bioenrichment analysis. Moreover, the anti-MIRI effects of PF (30, 60 and 120 mg/kg) were investigated in vivo on rats for verification. The myocardial infarction area was assessed by TTC/Evans blue staining and morphological changes of tissues were evaluated using hematoxylin and eosin staining. The contents of myocardial enzymes and oxidation resistance were measured. The cell apoptosis was evaluated using TUNEL staining and the expression of proteins was estimated using Western Blot. In the results, the relevant targets and the biological processes of PF against MIRI were screened out, indicating its anti-MIRI potential pharmacological effects of PF. 120 mg/kg PF can shrink infarction area after ischemia/reperfusion, ameliorate pathological morphology in myocardial tissue, lower the levels of myocardial enzymes, and attenuate oxidative stress. Furthermore, PF could reduce the positive rate of TUNEL staining caused by MIRI. Moreover, 120 mg/kg PF could depress the protein levels of Bax, Caspase-3, Beclin-1 and Cathepsin B and increase the protein level of Bcl-2 on rats after reperfusion. In conclusion, Paeoniflorin has an anti-MIRI effect in rats via coordinate regulation of anti-oxidative stress, anti-apoptosis and inhibition of autophagy.

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