Role of oxidative stress in PKC-δ upregulation and cardioprotection induced by chronic intermittent hypoxia

2007 ◽  
Vol 292 (1) ◽  
pp. H224-H230 ◽  
Author(s):  
František Kolář ◽  
Jana Ježková ◽  
Patricie Balková ◽  
Jiří Břeh ◽  
Jan Neckář ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Infarct Size ◽  
Intermittent Hypoxia ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Ischemic Tolerance ◽  
Saline Control ◽  
Chronic Intermittent Hypoxia ◽  
Left Ventricular Myocardium ◽  
Area At Risk

The aim was to determine whether increased oxidative stress during the adaptation to chronic intermittent hypoxia (CIH) plays a role in the induction of improved cardiac ischemic tolerance. Adult male Wistar rats were exposed to CIH in a hypobaric chamber (7,000 m, 8 h/day, 5 days/wk, 24–30 exposures). Half of the animals received antioxidant N-acetylcysteine (NAC; 100 mg/kg) daily before the exposure; the remaining rats received saline. Control rats were kept under normoxia and treated in a corresponding manner. One day after the last exposure (and/or NAC injection), anesthetized animals were subject to 20 min of coronary artery occlusion and 3 h of reperfusion for determination of infarct size. In parallel subgroups, biochemical analyses of the left ventricular myocardium were performed. Adaptation to CIH reduced infarct size from 56.7 ± 4.5% of the area at risk in the normoxic controls to 27.7 ± 4.9%. NAC treatment decreased the infarct size in the controls to 42.0 ± 3.4%, but it abolished the protection provided by CIH (to 41.1 ± 4.9%). CIH decreased the reduced-to-oxidized glutathione ratio and increased the relative amount of PKC isoform-δ in the particulate fraction; NAC prevented these effects. The expression of PKC-ε was decreased by CIH and not affected by NAC. Activities of superoxide dismutase, catalase, and glutathione peroxidase were affected by neither CIH nor NAC treatment. It is concluded that oxidative stress associated with CIH plays a role in the development of increased cardiac ischemic tolerance. The infarct size-limiting mechanism of CIH seems to involve the PKC-δ-dependent pathway but apparently not the increased capacity of major antioxidant enzymes.

Increased expression and altered subcellular distribution of PKC-δ in chronically hypoxic rat myocardium: involvement in cardioprotection

2005 ◽  
Vol 288 (4) ◽  
pp. H1566-H1572 ◽  
Author(s):  
Jan Neckář ◽  
Irena Marková ◽  
František Novák ◽  
Olga Nováková ◽  
Ondrej Szárszoi ◽  
...  
Keyword(s):  
Infarct Size ◽  
Intermittent Hypoxia ◽  
Chronic Hypoxia ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia ◽  
Control Group ◽  
Left Ventricular Myocardium ◽  
High Dose ◽  
Area At Risk

We examined the role of protein kinase C (PKC) in the cardioprotective mechanism induced by long-term adaptation to chronic intermittent hypoxia. Adult male Wistar rats were exposed to hypobaric hypoxia of 7,000 m for 8 h/day, 5 days/wk; the total number of exposures was 24–32. A control group was kept under normoxic conditions. Western blot analysis of PKC isoforms-δ and -ε was performed in the cytosol and three particulate fractions of left ventricular myocardium. Infarct size was determined in open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion. The PKC inhibitors chelerythrine (1 or 5 mg/kg) or rottlerin (selective for PKC-δ isoform; 0.3 mg/kg) were administered intravenously as a single bolus 15 min before ischemia. Chronic hypoxia had no effect on the expression and distribution of PKC-ε. The relative amount of PKC-δ increased in the cytosol and nuclear-cytoskeletal, mitochondrial, and microsomal fractions of chronically hypoxic myocardium by 100%, 212%, 237%, and 146%, respectively, compared with corresponding normoxic values. Chronic hypoxia decreased the size of myocardial infarction (normalized to the area at risk) by about one-third on the average ( P < 0.05). Both doses of chelerythrine tended to reduce infarction in controls, and only the high dose completely abolished the improvement of ischemic tolerance in hypoxic hearts ( P < 0.05). Rottlerin attenuated the infarct size-limiting effect of chronic hypoxia ( P < 0.05), and it had no effect in controls. These results suggest that chronic intermittent hypoxia-induced cardioprotection in rats is partially mediated by PKC-δ; the contribution of other isoforms remains to be determined.

Antioxidant tempol suppresses heart cytosolic phospholipase A2α stimulated by chronic intermittent hypoxia

2017 ◽  
Vol 95 (8) ◽  
pp. 920-927 ◽  
Author(s):  
Petra Míčová ◽  
Martina Klevstig ◽  
Kristýna Holzerová ◽  
Marek Vecka ◽  
Jitka Žurmanová ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia ◽  
Acute Ischemia ◽  
Left Ventricular Myocardium ◽  
Ros Generation ◽  
Mrna Levels

Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia–reperfusion injury. Phospholipases A2(PLA2s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2(cPLA2α), its phosphorylated form (p-cPLA2α), calcium-independent (iPLA2), and secretory (sPLA2IIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PLA2s expression and phospholipid FA remodeling. While CIH did not affect PLA2s mRNA levels, it increased the total cPLA2α protein in cytosol and membranes (by 191% and 38%, respectively) and p-cPLA2α (by 23%) in membranes. On the contrary, both iPLA2and sPLA2IIA were downregulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced cPLA2α up-regulation and its phosphorylation on Ser505. Our results show that CIH diversely affect myocardial PLA2s and suggest that ROS are responsible for the activation of cPLA2α under these conditions.

No impact of protein phosphatases on connexin 43 phosphorylation in ischemic preconditioning

2008 ◽  
Vol 295 (5) ◽  
pp. H2106-H2112 ◽  
Author(s):  
Andreas Totzeck ◽  
Kerstin Boengler ◽  
Anita van de Sand ◽  
Ina Konietzka ◽  
Petra Gres ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Connexin 43 ◽  
Protein Phosphatases ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Low Flow ◽  
Confocal Laser ◽  
Left Ventricular Myocardium ◽  
Area At Risk

Cardiac connexin 43 (Cx43) is involved in infarct propagation, and the uncoupling of Cx43-formed channels reduces infarct size. Cx43-formed channels open upon Cx43 dephosphorylation, and ischemic preconditioning (IP) prevents the ischemia-induced Cx43 dephosphorylation. In addition to the sarcolemma, Cx43 is also present in the cardiomyocyte mitochondria. We now examined the interaction of Cx43 with protein phosphatases PP1α, PP2Aα, and PP2Bα and the role of such interaction for Cx43 phosphorylation in preconditioned myocardium. Infarct size (in %area at risk) in left ventricular anterior myocardium of Göttinger minipigs subjected to 90 min of low-flow ischemia and 120 min of reperfusion was 23.1 ± 2.7 [ n = 7, nonpreconditioned (NIP) group] and was reduced by IP to 10.0 ± 3.2 ( n = 6, P < 0.05). Mitochondrial and gap junctional Cx43 dephosphorylation increased after 85 min of ischemia in NIP myocardium, whereas Cx43 phosphorylation was preserved with IP. PP2Aα and PP1α, but not PP2Bα, were detected by Western blot analysis in the left ventricular myocardium. Cx43 coprecipitated with PP2Aα but not with PP1α. Although the total PP2Aα immunoreactivity (confocal laser scan) was increased to 154 ± 24% and 194 ± 13% of baseline ( P < 0.05) after 85 min of ischemia in NIP and IP myocardium, respectively, the PP2A activities were similar between the groups. The amount of PP2Aα coimmunoprecipitated with Cx43 remained unchanged. Only PP2Aα coprecipitates with Cx43 in pig myocardium. This interaction is not affected by IP, suggesting that PP2Aα is not involved in the prevention of the ischemia-induced Cx43 dephosphorylation by IP.

scholarly journals The cardioprotective effect persisting during recovery from cold acclimation is mediated by the β2-adrenoceptor pathway and Akt activation

2020 ◽  
Author(s):  
Veronika Tibenská ◽  
Aneta Marvanova ◽  
Barbara Elsnicová ◽  
Lucie Hejnová ◽  
Pavel Vebr ◽  
...  
Keyword(s):  
Infarct Size ◽  
Cold Acclimation ◽  
Glycogen Synthase ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Acute Administration ◽  
Akt Activation ◽  
Downstream Targets ◽  
Male Wistar Rats

The infarct size-limiting effect elicited by cold acclimation (CA) is accompanied by increased mitochondrial resistance and unaltered β1-adrenergic receptor (AR) signaling persisting for two weeks at room temperature. As the mechanism of CA-elicited cardioprotection is not fully understood we examined the role of the salvage β2-AR/Gi/Akt pathway. Male Wistar rats were exposed to CA (8 °C, 5 weeks), while the recovery group (CAR) was kept at 24 °C for additional 2 weeks. We show that the total number of myocardial β-ARs in the left ventricular myocardium did not change after CA but decreased after CAR. We confirmed the infarct size-limiting effect in both CA and CAR groups. Acute administration of β2-AR inhibitor ICI-118551 abolished the protective effect in the CAR group but had no effect in the control and CA groups. The inhibitory Giα1/2 and Giα3 proteins increased in the membrane fraction of the CAR group, and the p-AktSer473/Akt ratio also increased. Expression, phosphorylation, and mitochondrial location of the Akt target glycogen synthase kinase (GSK3β), were affected neither by CA nor by CAR. However, GSK3β translocated from the Z-disc to the H-zone after CA, and acquired its original location after CAR. Our data indicate that the cardioprotection observed after CAR is mediated by the β2-AR/Gi pathway and Akt activation. Further studies are needed to unravel downstream targets of the central regulators of the CA process and the downstream targets of the Akt protein after CAR.

scholarly journals Isoflurane Protects against Myocardial Infarction during Early Reperfusion by Activation of Phosphatidylinositol-3-Kinase Signal Transduction: Evidence for Anesthetic-induced Postconditioning in Rabbits

2005 ◽  
Vol 102 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Pascal C. Chiari ◽  
Martin W. Bienengraeber ◽  
Paul S. Pagel ◽  
John G. Krolikowski ◽  
Judy R. Kersten ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Coronary Occlusion ◽  
Minimum Alveolar Concentration ◽  
Left Ventricular ◽  
Saline Control ◽  
Phosphatidylinositol 3 Kinase ◽  
Area At Risk ◽  
Early Reperfusion ◽  
Phosphatidylinositol 3

Background Brief episodes of ischemia during early reperfusion after coronary occlusion reduce the extent of myocardial infarction. Phosphatidylinositol-3-kinase (PI3K) signaling has been implicated in this "postconditioning" phenomenon. The authors tested the hypothesis that isoflurane produces cardioprotection during early reperfusion after myocardial ischemia by a PI3K-dependent mechanism. Methods Pentobarbital-anesthetized rabbits (n = 80) subjected to a 30-min coronary occlusion followed by 3 h reperfusion were assigned to receive saline (control), three cycles of postconditioning ischemia (10 or 20 s each), isoflurane (0.5 or 1.0 minimum alveolar concentration), or the PI3K inhibitor wortmannin (0.6 mg/kg, intravenously) or its vehicle dimethyl sulfoxide. Additional groups of rabbits were exposed to combined postconditioning ischemia (10 s) and 0.5 minimum alveolar concentration isoflurane in the presence and absence of wortmannin. Phosphorylation of Akt, a downstream target of PI3K, was assessed by Western blotting. Results Postconditioning ischemia for 20 s, but not 10 s, reduced infarct size (P &lt; 0.05) (triphenyltetrazolium staining; 20 +/- 3% and 34 +/- 3% of the left ventricular area at risk, respectively) as compared with control (41 +/- 2%). Exposure to 1.0, but not 0.5, minimum alveolar concentration isoflurane decreased infarct size (21 +/- 2% and 43 +/- 3%, respectively). Wortmannin abolished the protective effects of postconditioning (20 s) and 1.0 minimum alveolar concentration isoflurane. Combined postconditioning (10 s) and 0.5 minimum alveolar concentration isoflurane markedly reduced infarct size (17 +/- 5%). This action was also abolished by wortmannin (44 +/- 2%). Isoflurane (1.0 minimum alveolar concentration) increased Akt phosphorylation after ischemia (32 +/- 6%), and this action was blocked by wortmannin. Conclusions Isoflurane acts during early reperfusion after prolonged ischemia to salvage myocardium from infarction and reduces the threshold of ischemic postconditioning by activating PI3K.

scholarly journals Curcumin prevents chronic intermittent hypoxia-induced myocardial injury

2020 ◽  
Vol 11 ◽  
pp. 204062232092210 ◽  
Author(s):  
Sophie Moulin ◽  
Claire Arnaud ◽  
Sophie Bouyon ◽  
Jean-Louis Pépin ◽  
Diane Godin-Ribuot ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Infarct Size ◽  
Er Stress ◽  
Intermittent Hypoxia ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Sleep Apnoea ◽  
Cardiac Response ◽  
Chronic Intermittent Hypoxia ◽  
Obstructive Sleep

Background: Chronic intermittent hypoxia (IH), the hallmark feature of obstructive sleep apnoea syndrome, contributes to infarct size enhancement after myocardial ischemia–reperfusion (I/R). Curcumin (Curc), the natural pigment of Curcuma longa, has been demonstrated to be beneficial in the context of myocardial injury. In this study, we assessed the effects of Curc on the maladaptive cardiac response to IH, and particularly on IH-induced hypoxia inducible factor-1 (HIF-1) expression, oxidative stress, inflammation, endoplasmic reticulum (ER) stress and apoptosis. Methods: Swiss/SV129 mice were exposed to normoxia or IH (21–5% FiO2, 60 s cycles, 8 h per day, for 21 days) and treated orally with Curc (100 mg kg−1 day−1, oral gavage) or its vehicle. Mice were then either euthanised for heart sampling in order to perform biochemical and histological analysis, or subjected to an in vivo ischemia-reperfusion protocol in order to measure infarct size. Results: IH increased nuclear HIF-1α expression and superoxide anion (O2.–) production as well as nuclear factor kappa B (NF-kB) p65, glucose-regulated protein (Grp78) and C/EBP homologous protein (CHOP) expression. IH also induced apoptosis and increased infarct size after I/R . The IH-induced HIF-1 activation, oxidative stress, inflammation, ER stress and apoptosis were abolished by chronic Curc treatment. Curc also significantly decreased infarct size only in mice exposed to IH. Conclusion: Curc prevents IH-induced myocardial cell death signalling. Curc might be used as a combined therapy with continuous positive airway pressure in sleep apnoea patients with high cardiovascular risk.

Oxidative Stress and Left Ventricular Function with Chronic Intermittent Hypoxia in Rats

2005 ◽  
Vol 172 (7) ◽  
pp. 915-920 ◽  
Author(s):  
Ling Chen ◽  
Elliot Einbinder ◽  
Qi Zhang ◽  
Jeffrey Hasday ◽  
C. William Balke ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Intermittent Hypoxia ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia

scholarly journals Intracardiac hemodynamics, infarct-limiting effects and myocardial expression of microRNA 223 after necroptosis inhibition in a rat model of heterotopic allogeneic heart transplantation

2019 ◽  
Vol 24 (6) ◽  
pp. 710-715
Author(s):  
Yu. V. Dmitriev ◽  
L. V. Vasina ◽  
M. M. Galagudza
Keyword(s):  
Infarct Size ◽  
Coronary Flow ◽  
Troponin I ◽  
Myocardial Infarct ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Control Group ◽  
Left Ventricular Myocardium ◽  
Myocardial Infarct Size ◽  
Intraventricular Pressure

Objective.To investigate the effect of necroptosis inhibition on the morphofunctional state of the myocardium and the expression of microRNA 223 after heterotopic allogeneic heart transplantation in rat.Design and methods. Twenty Wistar rats were examined in the study. Animals were divided into the following groups: 1) control (n = 7), 2) dimethyl sulfoxide (DMSO) (n = 6), 3) necrostatin-1s (n = 7). Necrostatin-1s was used as an inhibitor of necroptosis, which was administered intraperitoneally in DMSO solution 1 hour before the start of the experiment at a dose of 1,65 mg/kg. HTK solution cooled to 4 °C was used as a preservation solution. Two hours after heart arrest, the heart was heterotopically transplanted in the abdominal cavity of recipient rat using the scheme “aorta-aorta, pulmonary trunc-posterior vena cava”. Three hours later, intracardiac hemodynamics was assessed by recording the pressure in the left ventricle, heart rate and coronary flow rate in Langendorff-perfused heart. The expression level of microRNA 223–5p and –3p in left ventricular myocardium was assessed using real-time polymerase chain reaction. The plasma levels of troponin I were assessed by enzyme immunoassay. Myocardial infarct size was measured planimetrically at the end of the experiment by staining myocardium with triphenyltetrazolium chloride.Results. Inhibition of necroptosis significantly improved the morphofunctional state of the myocardium, which manifested in a decrease of myocardial infarct size in the necrostatin-1s group compared with the control group and DMSO group. Thus, in the necrostatin-1s group, myocardial infarct size was 25 ± 8,7 %, which was smaller than in the control and DMSO groups (56 ± 9,5 and 57 ± 8,7 %, respectively; p < 0,05). Also in the necrostatin-1s group, lower diastolic intraventricular pressure was recorded, as well as higher values of pulse intraventricular pressure and coronary flow rate than in control group and DMSO group (p < 0,05). Left ventricular myocardium in the necrostatin-1s group demonstrated higher expression of the antinecroptotic miRNA 223–5p and –3p as compared with the control and DMSO groups, as well as lower plasma levels of troponin I (p < 0,05).Conclusions.Pharmacological inhibition of necroptosis in heterotopically transplanted donor heart is accompanied by marked cardioprotective effects and increases the expression of antinecroptotic microRNA 223–5p and –3p. 

Sign in / Sign up

Export Citation Format

Share Document