Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation

2007 ◽  
Vol 292 (5) ◽  
pp. C1583-C1590 ◽  
Author(s):  
Marko Ljubkovic ◽  
Yasushi Mio ◽  
Jasna Marinovic ◽  
Anna Stadnicka ◽  
David C. Warltier ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Atp Synthesis ◽  
Mitochondrial Uncoupling ◽  
Pharmacological Agents ◽  
Mitochondrial Redox State ◽  
Cardioprotective Effects ◽  
Isoflurane Treatment ◽  
Mild Uncoupling

Ischemic cardiac injury can be substantially alleviated by exposing the heart to pharmacological agents such as volatile anesthetics before occurrence of ischemia-reperfusion. A hallmark of this preconditioning phenomenon is its memory, when cardioprotective effects persist even after removal of preconditioning stimulus. Since numerous studies pinpoint mitochondria as crucial players in protective pathways of preconditioning, the aim of this study was to investigate the effects of preconditioning agent isoflurane on the mitochondrial bioenergetic phenotype. Endogenous flavoprotein fluorescence, an indicator of mitochondrial redox state, was elevated to 195 ± 16% of baseline upon isoflurane application in intact cardiomyocytes, indicating more oxidized state of mitochondria. Isoflurane treatment also elicited partial dissipation of mitochondrial transmembrane potential, which remained depolarized even after anesthetic withdrawal (tetramethylrhodamine fluorescence intensity declined to 83 ± 3 and 81 ± 7% of baseline during isoflurane exposure and washout, respectively). Mild uncoupling, with preserved ATP synthesis, was also detected in mitochondria that were isolated from animals that had been previously preconditioned by isoflurane in vivo, revealing its memory nature. These mitochondria, after exposure to hypoxia and reoxygenation, exhibited better preserved respiration and ATP synthesis compared with mitochondria from nonpreconditioned animals. Partial mitochondrial depolarization was paralleled by a diminished Ca2+ uptake into isoflurane-treated mitochondria, as indicated by the reduced increment in rhod-2 fluorescence when mitochondria were challenged with increased Ca2+ (180 ± 24 vs. 258 ± 14% for the control). In conclusion, isoflurane preconditioning elicits partial mitochondrial uncoupling and reduces mitochondrial Ca2+ uptake. These effects are likely to reduce the extent of the mitochondrial damage after the hypoxic stress.

scholarly journals PPARγ-Independent Side Effects of Thiazolidinediones on Mitochondrial Redox State in Rat Isolated Hearts

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 252 ◽  
Author(s):  
Matthias L. Riess ◽  
Reem Elorbany ◽  
Dorothee Weihrauch ◽  
David F. Stowe ◽  
Amadou K.S. Camara
Keyword(s):  
Redox State ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Brown Norway ◽  
Mitochondrial Uncoupling ◽  
Norway Rat ◽  
Isolated Hearts ◽  
Mitochondrial Redox State ◽  
Pparγ Agonists ◽  
Brown Norway Rat

The effect of anti-diabetic thiazolidinediones (TZDs) on contributing to heart failure and cardiac ischemia/reperfusion (IR) injury is controversial. In this study we investigated the effect of select TZDs on myocardial and mitochondrial function in Brown Norway rat isolated hearts. In a first set of experiments, the TZD rosiglitazone was given acutely before global myocardial IR, and pre- and post-IR function and infarct size were assessed. In a second set of experiments, different concentrations of rosiglitazone and pioglitazone were administered in the presence or absence of the specific PPARγ antagonist GW9662, and their effects on the mitochondrial redox state were measured by online NADH and FAD autofluorescence. The administration of rosiglitazone did not significantly affect myocardial function except for transiently increasing coronary flow, but it increased IR injury compared to the control hearts. Both TZDs resulted in dose-dependent, reversible increases in mitochondrial oxidation which was not attenuated by GW9662. Taken together, these data suggest that TZDs cause excessive mitochondrial uncoupling by a PPARγ-independent mechanism. Acute rosiglitazone administration before IR was associated with enhanced cardiac injury. If translated clinically, susceptible patients on PPARγ agonists may experience enhanced myocardial IR injury by mitochondrial dysfunction.

Abstract MP247: Mitochondrial Complex V Is Regulated By GRK2 In The Heart

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kimberly Ferrero ◽  
Jessica M Pfleger ◽  
Kurt Chuprun ◽  
Eric Barr ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Cardiac Injury ◽  
Atp Synthesis ◽  
Cardiac Metabolism ◽  
Neonatal Rat ◽  
Interacting Proteins ◽  
Atp Production

The GPCR kinase GRK2 is highly expressed the heart; importantly, during cardiac injury or heart failure (HF) both levels and activity of GRK2 increase. The role of GRK2 during HF is canonically studied upstream of β-adrenergic desensitization. However, GRK2 has a large interactome and noncanonical functions for this kinase are being uncovered. We have discovered that in the heart, GRK2 translocates to mitochondria ( mtGRK2 ) following injury and is associated with negative effects on cardiac metabolism. Thus, we have sought to identify the mechanism(s) by which GRK2 can regulate mitochondrial function. We hypothesize that mtGRK2 interacts with proteins which regulate bioenergetics and substrate utilization, and this never-before-described role may partially explain the altered mitochondrial phenotype seen following cardiac injury or HF. Stress-induced mitochondrial translocation of GRK2 was validated in neonatal rat ventricular myocytes, murine heart tissue and a cardiac-derived cell line. Consequently, the GRK2 interactome was mapped basally and under stress conditions in vitro, in vivo , and with tagged recombinant peptides. GRK2-interacting proteins were isolated via immunoprecipitation and analyzed via liquid chromatography-mass spectroscopy (LCMS). Proteomics analysis (IPA; Qiagen) identified mtGRK2 interacting proteins which were also involved in mitochondrial dysfunction. Excitingly, Complexes I, II, IV and V (ATP synthase) of the electron transport chain (ETC) were identified in the subset of mtGRK2-dysfunction partners. Several mtGRK2-ETC interactions were increased following stress, particularly those in Complex V. We further established that mtGRK2 phosphorylates some of the subunits of Complex V, particularly the ATP synthase barrel which is critical for ATP production in the heart. Specific amino acid residues on these subunits have been identified using PTM-LCMS and are currently being validated in a murine model of myocardial infarction. To support these data, we have also determined that alterations in either the levels or kinase activity of GRK2 appear to alter the enzymatic activity of Complex V in vitro , thus altering ATP production. In summary, the phosphorylation of the ATP synthesis machinery by mtGRK2 may be regulating some of the phenotypic effects of injured or failing hearts such as increased ROS production and reduced fatty acid metabolism. Research is ongoing in our lab to elucidate the novel role of GRK2 in regulating mitochondrial bioenergetics and cell death, thus uncovering an exciting, druggable novel target for rescuing cardiac function in patients with injured and/or failing hearts.

scholarly journals Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Changsheng Nai ◽  
Haochen Xuan ◽  
Yingying Zhang ◽  
Mengxiao Shen ◽  
Tongda Xu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Signaling Pathway ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Myocardial Infarct Size ◽  
Akt Signaling Pathway ◽  
Cardioprotective Effects

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.

scholarly journals Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia–reperfusion Injury in Rodents

2016 ◽  
Vol 125 (6) ◽  
pp. 1171-1180 ◽  
Author(s):  
Yao Lu ◽  
Honit Piplani ◽  
Stacy L. McAllister ◽  
Carl M. Hurt ◽  
Eric R. Gross
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
In Vivo Model

Abstract Background Recent evidence suggests that cross talk exists between cellular pathways important for pain signaling and ischemia–reperfusion injury. Here, the authors address whether the transient receptor potential ankyrin 1 (TRPA1) channel, important in pain signaling, is present in cardiac myocytes and regulates cardiac ischemia–reperfusion injury. Methods For biochemical analysis of TRPA1, techniques including quantitative polymerase chain reaction, Western blot, and immunofluorescence were used. To determine how TRPA1 mediates cellular injury, the authors used an in vivo model of rat cardiac ischemia–reperfusion injury and adult rat–isolated cardiac myocytes subjected to hypoxia–reoxygenation. Results The authors’ biochemical analysis indicates that TRPA1 is within the cardiac myocytes. Further, using a rat in vivo model of cardiac injury, the TRPA1 activators ASP 7663 and optovin reduce myocardial injury (45 ± 5%* and 44 ± 8%,* respectively, vs. control, 66 ± 6% infarct size/area at risk; n = 6 per group; mean ± SD; *P < 0.001). TRPA1 inhibition also blocked the infarct size–sparing effects of morphine. In isolated cardiac myocytes, the TRPA1 activators ASP 7663 and optovin reduce cardiac myocyte cell death when given during reoxygenation (20 ± 3%* and 22 ± 4%* vs. 36 ± 3%; percentage of dead cells per field, n = 6 per group; mean ± SD; *P < 0.05). For a rat in vivo model of cardiac injury, the infarct size–sparing effect of TRPA1 activators also occurs during reperfusion. Conclusions The authors’ data suggest that TRPA1 is present within the cardiac myocytes and is important in regulating myocardial reperfusion injury. The presence of TRPA1 within the cardiac myocytes may potentially explain why certain pain relievers that can block TRPA1 activation, such as cyclooxygenase-2 inhibitors or some nonsteroidal antiinflammatory drugs, could be associated with cardiovascular risk.

Cardioprotective Effects of Flocalin in In Vivo Experiments: Influence of the Hemodynamic and on the Damage of Myocardium under Ischemia-Reperfusion

2010 ◽  
Vol 1 (3) ◽  
pp. 211-218 ◽  
Author(s):  
Ruslan B. Strutynskyi ◽  
Ateksandr P. Neshcheret ◽  
Lesya V. Tumanovska ◽  
Roman A. Rovenets ◽  
Alexey A. Moibenko
Keyword(s):  
Ischemia Reperfusion ◽  
In Vivo Experiments ◽  
Cardioprotective Effects

Abstract MP133: Development of β-arrestin-biased Positive Allosteric Modulators for the β 1 Adrenergic Receptor

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Jialu Wang ◽  
Ilhan Gokhan ◽  
Xinyu Xiong ◽  
Alem W Kahsai ◽  
Haoran Jiang ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
New Drugs ◽  
Artery Ligation ◽  
Biased Agonism ◽  
Receptor Biology ◽  
Induced Apoptosis

The β 1 adrenergic receptor (β 1 AR) is a central regulator of cardiac function and an important therapeutic target for cardiac diseases. Two emerging areas of receptor biology are biased agonism: ligand directed selective engagement of a receptor toward either a G protein or β-arrestin transducer; and allosteric modulation: ligands that bind to topographically distinct sites on the receptor to modulate its activity. Advances in these areas have the potential to yield new drugs that precisely enhance cardioprotective effects while limiting untoward detrimental actions. Compound 6 (Cmpd6) is a newly discovered positive allosteric modulator (PAM) for the β 2 AR. Interestingly, we now show that Cmpd6 has the unique property to enhance the binding affinity of the β-arrestin-biased agonist carvedilol to both the β 2 AR and the β 1 AR, while having minimal effect on the affinity of a panel of agonists and antagonists of the β 1 AR. We further tested the effect of Cmpd6 on β 1 AR signaling induced by a broad range of ligands. Cmpd6 selectively enhanced carvedilol-stimulated ERK activation in a β-arrestin-dependent signaling fashion, while having no effect on carvedilol-induced G protein-dependent cAMP production. To test the in vivo effect of Cmpd6 on cardiac injury, mice were pretreated with carvedilol with or without Cmpd6, then underwent ischemia/reperfusion through the left anterior descending artery ligation. Cell apoptosis was assessed by TUNEL. Carvedilol decreased the level of I/R-induced apoptosis compared to the vehicle-treated animals, and Cmpd6 significantly positively enhanced the anti-apoptotic effects of carvedilol. In conclusion, we identified Cmpd6 as a potential β-arrestin-biased PAM for the β 1 AR that enhances the cardioprotective effect of carvedilol. Ongoing studies will test Cmpd6 on heart failure post myocardial infarction.

Cardioprotective actions of endogenous IL-10 are independent of iNOS

2001 ◽  
Vol 281 (1) ◽  
pp. H48-H52 ◽  
Author(s):  
Steven P. Jones ◽  
Steven D. Trocha ◽  
David J. Lefer
Keyword(s):  
Myocardial Ischemia ◽  
Inflammatory Responses ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
Interleukin 10 ◽  
Wild Type ◽  
Tissue Samples ◽  
Cardioprotective Effects

Myocardial ischemia-reperfusion (I/R) is a well-known stimulus for acute inflammatory responses that promote cell death and impair pump function. Interleukin-10 (IL-10) is an endogenous, potent anti-inflammatory cytokine. Recently, it has been proposed that IL-10 inhibits inducible nitric oxide synthase (iNOS) activity after myocardial I/R and consequently exerts cardioprotective effects. However, whether this actually occurs remains unclear. To test this hypothesis, we utilized iNOS-deficient (−/−), IL-10 −/−, and IL-10/iNOS −/− mice to examine the potential mechanism of IL-10-mediated cardioprotection after myocardial I/R. Wild-type, iNOS −/−, IL-10 −/−, and IL-10/iNOS −/− mice were subjected to in vivo myocardial ischemia (30 min) and reperfusion (24 h). Deficiency of iNOS alone did not significantly alter the extent of myocardial necrosis compared with wild-type mice. We found that deficiency of IL-10 resulted in a significantly ( P < 0.05) larger infarct size than that in wild-type hearts. Interestingly, deficiency of both IL-10 and iNOS yielded significantly ( P < 0.01) larger myocardial infarct sizes compared with wild-type animals. Histological examination of myocardial tissue samples revealed augmented neutrophil infiltration into the I/R myocardium of IL-10 −/− and IL-10/iNOS −/− mice compared with hearts of wild-type mice. These results demonstrate that 1) deficiency of endogenous IL-10 exacerbates myocardial injury after I/R; 2) the cardioprotective effects of IL-10 are not dependent on the presence or absence of iNOS; and 3) deficiency of IL-10 enhances the infiltration of neutrophils into the myocardium after I/R.

Activation of estrogen receptor-α protects the in vivo rabbit heart from ischemia-reperfusion injury

2005 ◽  
Vol 289 (5) ◽  
pp. H2039-H2047 ◽  
Author(s):  
Erin A. Booth ◽  
Nabeel R. Obeid ◽  
Benedict R. Lucchesi
Keyword(s):  
Estrogen Receptor ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rabbit Model ◽  
Experimental Studies ◽  
Cardioprotective Effects

The estrogen receptor (ER) mediates estrogenic activity in a variety of organs, including those in the reproductive, cardiovascular, immune, and central nervous systems. Experimental studies have demonstrated that 17β-estradiol (E2) protects the heart from ischemia-reperfusion injury. Two estrogen receptors, ERα and ERβ, mediate the actions of estrogen; however, it is not certain which ER mediates the cardioprotective effects of E2. In the present study, the ER-selective agonists 4,4′,4′′-[4-propyl-(1 H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; ERα) and 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ERβ) were assessed for their cardioprotective potential in an in vivo rabbit model of ischemia-reperfusion injury. Anesthetized female rabbits were administered PPT (3 mg/kg), DPN (3 mg/kg), E2 (20 μg/rabbit), or vehicle intravenously 30 min before a 30-min occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Acute treatment with E2 (17.7 ± 2.9%; P < 0.001) and PPT (18.1 ± 2.9%; P < 0.001), but not DPN (45.3 ± 2.4%) significantly decreased infarct size as a percent of area at risk compared with vehicle (45.3 ± 2.4%). Coadministration of PPT or E2 with the ER antagonist ICI-182,780 limited the infarct size-sparing effect of the compounds (43.8 ± 6.6% and 40.6 ± 5.7% respectively, expressed as a percentage of risk region). PPT reduced the release of cardiac-specific troponin-I and reduced the tissue deposition of the membrane attack complex and C-reactive protein similar to that of E2. The results indicate that activation of ERα, but not ERβ, is required for the observed cardioprotective effects of E2.

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