scholarly journals EFHD1 ablation reduces cardiac mitoflash activation and protects cardiomyocytes from ischemia.

2021 ◽  
Author(s):  
David R Eberhardt ◽  
Sandra H Lee ◽  
Xue Yin ◽  
Anthony M Balynas ◽  
Emma Rekate ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Cardiac Injury ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Cardiac Mitochondria ◽  
Hypoxic Injury ◽  
Cardiac Phenotype ◽  
Ef Hand

Altered levels of intracellular calcium (Ca2+) are a highly prevalent feature in different forms of cardiac injury, producing changes in contractility, arrhythmias, and mitochondrial dysfunction. In cardiac ischemia-reperfusion injury, mitochondrial Ca2+ overload leads to pathological production of reactive oxygen species (ROS), activates the permeability transition, and cardiomyocyte death. Here we investigated the cardiac phenotype caused by deletion of EF-hand domain-containing protein D1 (Efhd1-/-), a Ca2+-binding mitochondrial protein whose function is poorly understood. Efhd1-/- mice are viable and have no adverse cardiac phenotypes. They feature reductions in basal ROS levels and mitoflash events, both important precursors for mitochondrial injury, though cardiac mitochondria have normal susceptibility to Ca2+ overload. Notably, we also find that Efhd1-/- mice and their cardiomyocytes are resistant to hypoxic injury.

scholarly journals A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury

2010 ◽  
Vol 298 (1) ◽  
pp. H16-H23 ◽  
Author(s):  
Jean Chrisostome Bopassa ◽  
Mansoureh Eghbali ◽  
Ligia Toro ◽  
Enrico Stefani
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Rate Pressure Product ◽  
Triphenyltetrazolium Chloride ◽  
Mptp Opening ◽  
Mitochondria Permeability Transition Pore

Several studies have recently demonstrated that G protein-coupled receptor 30 (GPER) can directly bind to estrogen and mediate its action. We investigated the role and the mechanism of estrogen-induced cardioprotection after ischemia-reperfusion using a specific GPER agonist G1. Isolated hearts from male mice were perfused using Langendorff technique with oxygenated (95% O2 and 5% CO2) Krebs Henseleit buffer (control), with G1 (1 μM), and G1 (1 μM) together with extracellular signal-regulated kinase (Erk) inhibitor PD-98059 (5μM). After 20 min of perfusion, hearts were subjected to 20 min global normothermic (37°C) ischemia followed by 40 min reperfusion. Cardiac function was measured, and myocardial necrosis was evaluated by triphenyltetrazolium chloride staining at the end of the reperfusion. Mitochondria were isolated after 10 min of reperfusion to assess the Ca2+ load required to induce mitochondria permeability transition pore (mPTP) opening. G1-treated hearts developed better functional recovery with higher rate pressure product (RPP, 6140 ± 264 vs. 2,640 ± 334 beats·mmHg−1·min−1, P < 0.05). The infarct size decreased significantly in G1-treated hearts (21 ± 2 vs. 46 ± 3%, P < 0.001), and the Ca2+ load required to induce mPTP opening increased (2.4 ± 0.06 vs. 1.6 ± 0.11 μM/mg mitochondrial protein, P < 0.05) compared with the controls. The protective effect of G1 was abolished in the presence of PD-98059 [RPP: 4,120 ± 46 beats·mmHg−1·min−1, infarct size: 53 ± 2%, and Ca2+ retention capacity: 1.4 ± 0.11 μM/mg mitochondrial protein ( P < 0.05)]. These results suggest that GPER activation provides a cardioprotective effect after ischemia-reperfusion by inhibiting the mPTP opening, and this effect is mediated by the Erk pathway.

Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance

2007 ◽  
Vol 292 (2) ◽  
pp. R920-R926 ◽  
Author(s):  
Prasad V. G. Katakam ◽  
James E. Jordan ◽  
James A. Snipes ◽  
Christina D. Tulbert ◽  
Allison W. Miller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Manganese Superoxide Dismutase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Cardiac Injury ◽  
Mitochondrial Oxidative Stress ◽  
Isolated Mitochondria

Insulin resistance (IR) precedes the onset of Type 2 diabetes, but its impact on preconditioning against myocardial ischemia-reperfusion injury is unexplored. We examined the effects of diazoxide and ischemic preconditioning (IPC; 5-min ischemia and 5-min reperfusion) on ischemia (30 min)-reperfusion (240 min) injury in young IR Zucker obese (ZO) and lean (ZL) rats. ZO hearts developed larger infarcts than ZL hearts (infarct size: 57.3 ± 3% in ZO vs. 39.2 ± 3.2% in ZL; P < 0.05) and also failed to respond to cardioprotection by IPC or diazoxide (47.2 ± 4.3% and 52.5 ± 5.8%, respectively; P = not significant). In contrast, IPC and diazoxide treatment reduced the infarct size in ZL hearts (12.7 ± 2% and 16.3 ± 6.7%, respectively; P < 0.05). The mitochondrial ATP-activated potassium channel (KATP) antagonist 5-hydroxydecanoic acid inhibited IPC and diazoxide-induced preconditioning in ZL hearts, whereas it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared with ZL (73 ± 9% in ZL vs. 39 ± 9% in ZO; P < 0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared with ZL hearts. Electron micrographs of ZO hearts revealed a decreased number of mitochondria accompanied by swelling, disorganized cristae, and vacuolation. Immunoblots of mitochondrial protein showed a modest increase in manganese superoxide dismutase in ZO hearts. Thus obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury, which is mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial KATP.

Abstract 13879: Ischemic Postconditioning Confers Cardioprotection through Adiponectin-dependent Mitochondrial STAT3 Activation in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Haobo Li ◽  
Michael G Irwin ◽  
Zhengyuan Xia
Keyword(s):  
Cell Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Systolic Pressure ◽  
Gene Knockdown ◽  
Area At Risk ◽  
In Cells

Introduction: Signal transducer and activator of transcription 3 (STAT3) plays a key role in postconditioning (IPo) mediated protection against myocardial ischemia reperfusion injury, but the mechanism by which IPo activates STAT3 is unknown. Adiponectin (APN), a protein with anti-ischemic properties, activates STAT3. We hypothesized that IPo activates mitochondrial STAT3 (MitoSTAT3) via APN signaling. Methods and Results: Wild type (WT) and APN knockout (KO) mice were either sham operated or subjected to 30 min of coronary artery occlusion followed by 2 hours of reperfusion with or without IPo (3 cycles of 10 seconds reperfusion and 10 seconds reocclusion; n=8/group). At the end of reperfusion, KO mice exhibited more severe myocardial injury evidenced as increased infarct size (% of area at risk) 49.2±2.0 vs WT 39.4±3.5, P <0.01; plasma troponin I (ng/ml): KO 72.8±7.6 vs WT 45.7±4.0, P <0.01; worse cardiac function (lower dP/dt max and end-systolic pressure-volume relation, P <0.05); more severely impaired mitochondrial function (reductions in complex IV and complex V protein expression) and more severe reduction of MitoSTAT3 phosphorylation (activation) at site Ser727, P <0.01. IPo significantly attenuated post-ischemic cardiac injury and dysfunction with a concomitant increase in phosphorylated MitoSTAT3 and attenuation of mitochondrial dysfunction in WT (all P <0.05) but not in KO mice. In cultured cardiac H9C2 cells, hypoxic postconditioning (HPo, 3 cycles of 5 min hypoxia and 5 min reoxygenation) significantly attenuated hypoxia/reoxygenation (HR, 3 hours hypoxia/3 hours reoxygenation) induced cell injury (increased apoptotic cell death as % of HR): HR 100.2±0.4 vs HPo 78.2±4.8, P <0.05) and reduced mitochondrial transmembrane potential (% total cells, HR 37.2±4.9 vs HPo 23.5±3.7, P <0.01). APN, adiponectin receptor 1 (AdipoR1), or STAT3 gene knockdown but not AdipoR2 gene knockdown, respectively, abolished HPo cellular protection (all P <0.05 vs. HPo). APN supplementation (10μg/ml) restored HPo protection in cells with APN knockdown but not in cells with AdipoR1or STAT3 gene knockdown. Conclusion: Adiponectin and AdipoR1 signaling are required for IPo to activate myocardial mitochondrial STAT3 to confer cardioprotection.

scholarly journals Kolaviron attenuates ischemia/reperfusion injury in the stomach of rats

2018 ◽  
Vol 43 (1) ◽  
pp. 30-37 ◽  
Author(s):  
Olugbenga Adeola Odukanmi ◽  
Adeola Temitope Salami ◽  
Onaara Peter Ashaolu ◽  
Adeoti Gbemisola Adegoke ◽  
Samuel Babafemi Olaleye
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Oxygen Species ◽  
Male Adult ◽  
Garcinia Kola ◽  
Neutrophil Lymphocyte Ratio ◽  
Nitric Oxide Level

Kolaviron (KV), an active complex of at least 3 compounds in Garcinia kola seed, which is known for its antioxidant and anti-inflammatory activity, was investigated for its gastro-protective effect in the stomach of rats subjected to ischemia/reperfusion-induced gastric ulceration. Male adult Wistar rats (180–210 g) were randomized into 6 groups (n = 15) as follows: (i) control, (ii) ulcerated untreated (UU), (iii) KV alone (KVA), (iv) KV + ulcer (KVU), (v) ulcer + KV (UKV), and (vi) ulcer + omeprazole (20 mg/kg). Ulcer was induced through ischemia/reperfusion method after 2 weeks of daily oral KV (100 mg/kg). Rats were weighed daily, and gastric acid secretion, ulcer scores, hematological, biochemical, and histological variables were assessed 1 h after induction at 3 and 7 days post-ulceration. Body weight decreased in KVA (179.1 ± 1.6 g), and KVU (170.1 ± 2.2 g) compared with UU (199.0 ± 1.4 g). Gastric acid secretion decreased significantly in KVU after 1 h and 3 days post-ulceration (0.27 ± 0.03 mEq/L; 0.49 ± 0.02 mEq/L) compared with UU (0.60 ± 0.06 mEq/L; 0.85 ± 0.29 mEq/L), respectively. There was significant reduction in neutrophil/lymphocyte ratio of KVA (0.29 ± 0.06) and KVU (0.35 ± 0.02) compared with UU (0.54 ± 0.04). Malondialdehyde level decreased significantly with concomitant increase in anti-oxidative activities and nitric oxide level in the KV treated groups (KVA, KVU, UKV) compared with UU. In conclusion, treatment with KV protects the stomach by reducing gastric acid secretion, promoting antioxidant activity and suppressing action of reactive oxygen species.

Abstract 17188: Cryoem Analysis in Cardiac Isolated Mitochondria Reveals New Insights for CsA and mPTP Activation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Jasiel O Strubbe ◽  
Jason Schrad ◽  
James F Conway ◽  
Kristin N Parent ◽  
Jason N Bazil
Keyword(s):  
Time Course ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Granule Formation ◽  
Membrane Rupture ◽  
Mptp Opening

Excessive Ca 2+ accumulation is the main source of cardiac tissue and cell death during myocardial ischemia-reperfusion injury (IR injury) and myocardial infarction. Calcium dysregulation and overload leads to mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, catastrophic energy failure, and opening of the cyclosporine A-sensitive mitochondrial permeability transition pore (mPTP). Mitochondrial Ca 2+ accumulation also results in the formation of amorphous Ca 2+ -phosphate granules localized in the mitochondrial matrix. These amorphous electron-dense granules are main components of the mitochondrial Ca 2+ sequestration and buffering system by mechanisms not yet well understood. The two aims of the present study are to test the relationship of Ca 2+ -phosphate granule size and number in cardiac mitochondria 1) exposed to a bolus calcium sufficient to elicit permeabilization and 2) whether CsA-treated mitochondria alters granule formation and size. A time course series of CryoEM images was analyzed to follow the permeabilization process. CryoEM results showed that mitochondrial incubated for longer time-courses have increased number of small granules (40 - 110 nm), swelling, membrane rupture and induction of mPTP opening. Conversely, shorter incubation time resulted in less granules per mitochondrion yet of similar size (35 - 90 nm). CsA- treated mitochondria, on the other hand, showed bigger phosphate granules (120 - 160 nm), and both lower granules per mitochondria and mPTP opening susceptibility. These results suggest a novel mechanism for CsA in which Ca 2+ -phosphate granule sizes are enhanced while maintaining fewer per mitochondrion. This effect may explain why CsA-treated mitochondria have higher calcium tolerance, delayed Ca 2+ -dependent opening of the mPTP, and protects against reperfusion-induced myocardial necrosis.

Abstract 203: Regulation of Lipid Phosphate Phosphatase 3 in Cardiac Ischemia/Reperfusion Injury and Hypertrophy

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Mini Chandra ◽  
Jonathan Fox ◽  
Wayne Orr ◽  
Christopher Kevil ◽  
Sumitra Miriyala ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Negative Regulator ◽  
Cardiomyocyte Hypertrophy ◽  
Acute Mi ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphatases ◽  
Old Mice

Generation of reactive oxygen species (ROS) has been implicated in myocardial infarction (MI), stroke and sudden cardiac death. Mitochondrial respiration is a major source of ROS production and lipids regulate mitochondrial oxidative metabolism and homeostasis through effects on mitochondrial fusion and fission and on the activity of mitochondrial membrane proteins. Lipid phosphate phosphatases (LPPs) control the conversion of bioactive lipid phosphates to their dephosphorylated counterparts. These include phosphatidic acid (PA), and lysophosphatidic acid (LPA). Oxidative stress was identified to transactivate microRNA-92a, which is a negative regulator of LPP3. We found that LPP3 expression was markedly down regulated in ischemic regions after ischemia/reperfusion (I/R) injury. We observed a similar trend in the myocardium from patients with acute MI at 24h. Our in vitro studies indicate that overexpression of LPP3 protects the cardiomyocyte against ROS-induced cardiac injury and reduction of LPP3 by conditional specific cardiac knockout of the LPP3 gene in mice increases cardiac dysfunction and mortality. These mice are viable and fertile but showed increased mortality ~8 months (Fig1). Blood pressure was similar in LPP3 fl/fl (96 ± 9 mmHg; n = 19) and Myh6- LPP3 Δ mice (92 ± 7 mmHg; n = 19), although heart rates were significantly higher in Myh6- LPP3 Δ 3 month old mice (642 ± 21 bpm, compared to LPP3 fl/fl with 600± 17 bpm; P<0.001). Knockdown of LPP3 enhanced cardiomyocyte hypertrophy induced by LPA based on analysis of sarcomere organization, cell surface area, levels of fetal genes ANP and BNP, and ANF release from nuclei, which are hallmarks of cardiomyocyte hypertrophy, indicating that LPP3 negatively regulates cardiomyocyte hypertrophy induced by LPA.

scholarly journals Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury

2019 ◽  
Vol 11 (3) ◽  
pp. 292-297 ◽  
Author(s):  
Jonathan E. Palmer ◽  
Breanna M. Brietske ◽  
Tyler C. Bate ◽  
Erik A. Blackwood ◽  
Manasa Garg ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Selective Activation
Sign in / Sign up

Export Citation Format

Share Document