scholarly journals ZP2495 Protects against Myocardial Ischemia/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK-FoxO3a Signal Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Shuang Li ◽  
Hao Wu ◽  
Dong Han ◽  
Mingming Zhang ◽  
Na Li ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cardiac Function ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Ros Generation ◽  
Mitochondrial Morphology ◽  
Signal Pathways ◽  
The Impact

Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr+/lepr+ (BKS) and db/db mice received 4-week treatment of glucagon, ZP131 (GLP-1 receptor agonist), or ZP2495, followed by cardiac I/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131. In vitro study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high-glucose and simulated I/R injury conditions, the effects of which were weaker in the ZP131 group. Furthermore, the expressions of Akt, FoxO3a, and AMPK phosphorylation were elevated by ZP2495 to a greater extent than that of ZP131. In conclusion, ZP2495 may contribute to the improvement of cardiac function and energy metabolism in db/db mice after myocardial I/R injury by improving mitochondrial function possibly through Akt/FoxO3a and AMPK/FoxO3a signal pathways.

Abstract P311: Blocking Succinate Release Enhances Mitochondrial Reactive Oxygen Species Generation And Worsens Ischemia-reperfusion Injury

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Alexander S Milliken ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Ros Generation ◽  
Ros Production ◽  
Succinate Oxidation ◽  
Fluorescence Measurements ◽  
Mitochondrial Ros ◽  
The Impact ◽  
Infarction Heart

Succinate is a metabolite that plays a central role in ischemia-reperfusion (IR) injury,which is relevant to myocardial infarction (heart attack) and stroke. Succinateaccumulates during ischemia and is rapidly consumed at reperfusion driving reactiveoxygen species (ROS) generation at complex-I (Cx-I) and III of the mitochondrial electrontransport chain. This ROS production triggers cell-death, leading to tissue necrosis.Although succinate oxidation has been extensively studied and exploited as a noveltherapeutic target, only 1/3 of the succinate accumulated in ischemia is oxidized atreperfusion, with the remaining 2/3 being released from the cell via monocarboxylatetransporter 1 (MCT1). Extracellular succinate is thought to be pro-inflammatory, and ithas been proposed that preventing succinate release may be therapeutically beneficial.To determine the impact of preventing succinate release on IR injury, we comparedfunctional recovery (i.e. rate x pressure product, RPP) and infarction (i.e. tissue necrosis)of Langendorff perfused mouse hearts treated with an MCT1 inhibitor, AR-C155858,versus vehicle control. This revealed that succinate retention worsens IR injury (i.e.increased infarction and decreased functional recovery) likely due to increased ROS. Totest this hypothesis, we utilized a Langendorff apparatus positioned within aspectrofluorimeter, which permits real-time fluorescence measurements in beatingmouse hearts. Using the mitochondria targeted superoxide probe, MitoSOX red tomeasure ROS production at reperfusion + AR-C155858, demonstrated that succinateretention leads to enhanced mitochondrial ROS generation at the onset of reperfusion.Overall, these results suggest that inhibiting succinate release in the context of IR injurymay not be a viable therapeutic approach, regardless of any downstream anti-inflammatory effects.

scholarly journals Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK–OPA1–ATP5A1 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Li-Zhen Qiu ◽  
Wei Zhou ◽  
Lan-Xin Yue ◽  
Yi-Hao Wang ◽  
Fei-Ran Hao ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Mitochondrial Function ◽  
Positive Inotropic Effect ◽  
Neonatal Rat ◽  
Inotropic Effect ◽  
Mitochondrial Morphology ◽  
Repeated Treatment ◽  
Α Subunit ◽  
Compound C ◽  
Cardiotonic Effect

Aconitine is attracting increasing attention for its unique positive inotropic effect on the cardiovascular system, but underlying molecular mechanisms are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the potential role of OPA1-mediated regulation of energy metabolism in the positive inotropic effect caused by repeated aconitine treatment and the possible mechanism involved. Our results showed that repeated treatment with low-doses (0–10 μM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in Neonatal Rat Ventricular Myocytes (NRVMs). Also, we first identified that no more than 5 μM of aconitine triggered an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, both of which were identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, with compound C (CC), an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via the AMPK–OPA1–ATP5A1 pathway and provide a possible explanation for the energy metabolism associated with cardiotonic effect induced by medicinal plants containing aconitine.

Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

2012 ◽  
Vol 90 (6) ◽  
pp. 811-823 ◽  
Author(s):  
Sri N. Batchu ◽  
Stephen B. Lee ◽  
Victor Samokhvalov ◽  
Ketul R. Chaudhary ◽  
Haitham El-Sikhry ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Left Ventricular ◽  
Ros Generation ◽  
The Novel ◽  
Active Metabolites ◽  
Developed Pressure

Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 µmol·L–1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 µmol·L–1) and sEH–/– mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol·L–1), or the plasma membrane KATP channels (pmKATP) inhibitor (glibenclamide, 10 µmol·L–1) abolished the improved recovery by BI00611953 (1 µmol·L–1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1∝ DNA binding, and delayed the loss of mitochondrial membrane potential (ΔΨm) caused by anoxia–reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

scholarly journals Capsaicin Alleviates the Deteriorative Mitochondrial Function by Upregulating 14-3-3η in Anoxic or Anoxic/Reoxygenated Cardiomyocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Yang Qiao ◽  
Tianhong Hu ◽  
Bin Yang ◽  
Hongwei Li ◽  
Tianpeng Chen ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Complex I ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Neonatal Rat ◽  
Ros Generation ◽  
Consumption Rates ◽  
Vitro Model ◽  
The Impact

Reactive oxygen species (ROS) are byproducts of a defective electron transport chain (ETC). The redox couples, GSH/GSSG and NAD+/NADH, play an essential role in physiology as internal defenses against excessive ROS generation by facilitating intracellular/mitochondrial (mt) redox homeostasis. Anoxia alone and anoxia/reoxygenation (A/R) are dissimilar pathological processes. In this study, we measured the impact of capsaicin (Cap) on these pathological processes using a primary cultured neonatal rat cardiomyocyte in vitro model. The results showed that overproduction of ROS was tightly associated with disturbed GSH/GSSG and NAD+/NADH suppressed mt complex I and III activities, decreased oxygen consumption rates, and elevated extracellular acidification rates. During anoxia or A/R period, these indices interact with each other causing the mitochondrial function to worsen. Cap protected cardiomyocytes against the different stages of A/R injury by rescuing NAD+/NADH, GSH/GSSG, and mt complex I/III activities and cellular energy metabolism. Importantly, Cap-mediated upregulation of 14-3-3η, a protective phosphoserine-binding protein in cardiomyocytes, ameliorated mt function caused by a disruptive redox status and an impaired ETC. In conclusion, redox pair, mt complex I/III, and metabolic equilibrium were significantly different in anoxia alone and A/R injury; Cap through upregulating 14-3-3η plays a protection against the above injury in cardiomyocyte.

scholarly journals TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

2015 ◽  
Vol 36 (5) ◽  
pp. 2072-2082 ◽  
Author(s):  
Peng Zhang ◽  
Yong Lu ◽  
Dong Yu ◽  
Dadong Zhang ◽  
Wei Hu
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Complex Activity ◽  
Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

scholarly journals Dihydromyricetin Ameliorates Cardiac Ischemia/Reperfusion Injury through Sirt3 Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Liping Wei ◽  
Xuseng Sun ◽  
Xin Qi ◽  
Yufan Zhang ◽  
Yuanyang Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
In Vitro Study ◽  
Vitro Study ◽  
Ampelopsis Grossedentata

During myocardial infarction, quickly opening the occluded coronary artery is a major method to save the ischemic myocardium. However, it also induces reperfusion injury, resulting in a poor prognosis. Alleviating the reperfusion injury improves the prognosis of the patients. Dihydromyricetin (DHM), a major component in the Ampelopsis grossedentata, has numerous biological functions. This study aims to clarify the effects of DHM under the ischemia/reperfusion (I/R) condition. We elucidated the role of Sirt3 in the cardiomyocyte response to DHM based on the hearts and primary cardiomyocytes. Cardiac function, mitochondrial biogenesis, and infarct areas were examined in the different groups. We performed Western blotting to detect protein expression levels after treatments. In an in vitro study, primary cardiomyocytes were treated with Hypoxia/Reoxygenation (H/R) to simulate the I/R. DHM reduced the infarct area and improved cardiac function. Furthermore, mitochondrial dysfunction was alleviated after DHM treatment. Moreover, DHM alleviated oxidative stress indicated by decreased ROS and MnSOD. However, the beneficial function of DHM was abolished after removing the Sirt3. On the other hand, the mitochondrial function was improved after DHM intervention in vitro study. Interestingly, Sirt3 downregulation inhibited the beneficial function of DHM. Therefore, the advantages of DHM are involved in the improvement of mitochondrial function and decreased oxidative stress through the upregulation of Sirt3. DHM offers a promising therapeutic avenue for better outcome in the patients with cardiac I/R injury.

Abstract 464: Dynamic Regulation of the Epidermal Growth Factor Receptor Protein Interactome via β1-adrenergic Receptor-mediated Transactivation in Cardiomyocytes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Jeanette Einspahr
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mitochondrial Function ◽  
Adrenergic Receptor ◽  
Growth Factor Receptor ◽  
Neonatal Rat ◽  
Mitochondrial Morphology ◽  
Epidermal Growth ◽  
The Impact

Heart Failure (HF) is a chronic, progressive condition wherein the heart cannot perfuse adequate amounts of blood and oxygen to meet the demands of metabolizing tissues. Gold standard HF therapeutics currently consist of a small repertoire of neurohormone modulators that still result in ~50% mortality within 5 years. Our ongoing goal is to develop new signaling modalities as refined HF therapeutics. We have shown that β1-adrenergic receptor (β1AR) stimulation rapidly induces epidermal growth factor receptor (EGFR)-dependent protein signaling responses in various regions of cardiomyocytes (CM). We hypothesize that differences in the subcellular localization and protein interactomes of EGFR following differential ligand stimulation modulate CM functions in distinct manners. To test this, we infected neonatal rat ventricular myocytes (NRVM) with adenoviruses encoding HA-β1AR and Flag-EGFR, stimulated them with vehicle, isoproterenol or EGF for 5 min and performed mass spectroscopy analysis of the Flag-EGFR immunoprecipitates. While hundreds of protein interactions were identified, one of the highly enriched subcellular groups belonged to mitochondrial proteins, for which there is no information regarding the role of EGFR in their regulation in CM. Via fractionation and digestion analyses, we have confirmed EGFR localization to the outer mitochondrial membrane in CM and have begun to assess the impact of EGFR on mitochondrial function. Transmission electron microcopy analysis of mitochondrial morphology show that CM-specific EGFR knockdown (CM-EGFR-KD) increases mitochondrial circularity and mitochondria/area without changes in other parameters including perimeter or cristae density, suggesting altered bioenergetic potential. Indeed, extracellular flux (Seahorse) analysis of CM-EGFR-KD versus control CM revealed that CM-EGFR-KD increased maximal and reserve capacities and a trend toward increased ATP production. Elucidating the mechanism(s) of EGFR localization to and association with proteins at CM mitochondria, as well as its impact on mitochondrial function normally or in response to catecholamine stimulation will provide insight into the potential utility of targeting mitochondrial EGFR to improve HF outcomes.

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