Potential interactions between iloprost and SIN-1 on platelet aggregation and myocardial infarct size in vivo

1999 ◽  
Vol 374 (1) ◽  
pp. 59-69 ◽  
Author(s):  
Keri A Aitchison ◽  
Susan J Coker
Keyword(s):  
Platelet Aggregation ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Potential Interactions

scholarly journals Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

2021 ◽  
Vol 9 ◽  
Author(s):  
Feng Tian ◽  
Ying Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemic Injury ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Myocardial Infarct Size ◽  
Hypoxic Injury

Our previous research has shown that type-2a Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) undergoes posttranscriptional oxidative modifications in cardiac microvascular endothelial cells (CMECs) in the context of excessive cardiac oxidative injury. However, whether SERCA2a inactivity induces cytosolic Ca2+ imbalance in mitochondrial homeostasis is far from clear. Mitofusin2 (Mfn2) is well known as an important protein involved in endoplasmic reticulum (ER)/mitochondrial Ca2+ tethering and the regulation of mitochondrial quality. Therefore, the aim of our study was to elucidate the specific mechanism of SERCA2a-mediated Ca2+ overload in the mitochondria via Mfn2 tethering and the survival rate of the heart under conditions of cardiac microvascular ischemic injury. In vitro, CMECs extracted from mice were subjected to 6 h of hypoxic injury to mimic ischemic heart injury. C57-WT and Mfn2KO mice were subjected to a 1 h ischemia procedure via ligation of the left anterior descending branch to establish an in vivo cardiac ischemic injury model. TTC staining, immunohistochemistry and echocardiography were used to assess the myocardial infarct size, microvascular damage, and heart function. In vitro, ischemic injury induced irreversible oxidative modification of SERCA2a, including sulfonylation at cysteine 674 and nitration at tyrosine 294/295, and inactivation of SERCA2a, which initiated calcium overload. In addition, ischemic injury-triggered [Ca2+]c overload and subsequent [Ca2+]m overload led to mPTP opening and ΔΨm dissipation compared with the control. Furthermore, ablation of Mfn2 alleviated SERCA2a-induced mitochondrial calcium overload and subsequent mito-apoptosis in the context of CMEC hypoxic injury. In vivo, compared with that in wild-type mice, the myocardial infarct size in Mfn2KO mice was significantly decreased. In addition, the findings revealed that Mfn2KO mice had better heart contractile function, decreased myocardial infarction indicators, and improved mitochondrial morphology. Taken together, the results of our study suggested that SERCA2a-dependent [Ca2+]c overload led to mitochondrial dysfunction and activation of Mfn2-mediated [Ca2+]m overload. Overexpression of SERCA2a or ablation of Mfn2 expression mitigated mitochondrial morphological and functional damage by modifying the SERCA2a/Ca2+-Mfn2 pathway. Overall, these pathways are promising therapeutic targets for acute cardiac microvascular ischemic injury.

Isoflurane Mimics Ischemic Preconditioning via Activation of KATPChannels 

1997 ◽  
Vol 87 (2) ◽  
pp. 361-370 ◽  
Author(s):  
Judy R. Kersten ◽  
Todd J. Schmeling ◽  
Paul S. Pagel ◽  
Garrett J. Gross ◽  
David C. Warltier
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Hemodynamic Effects ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride ◽  
Anesthetized Dogs

Background The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning. Methods Barbiturate-anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5-min LAD occlusions interspersed with 5-min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane-induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane. Results Myocardial infarct size was 25.3 +/- 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P < 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/- 2.0; isoflurane alone, 11.8 +/- 2.7; isoflurane and ischemic preconditioning, 5.1 +/- 1.9%). Isoflurane-induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/- 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/- 3.9%), but it abolished the protective effects of isoflurane (27.1 +/- 4.6%). Conclusions Isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.

PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts

2007 ◽  
Vol 293 (5) ◽  
pp. H2845-H2852 ◽  
Author(s):  
Rong Jiang ◽  
Amanda Zatta ◽  
Hajime Kin ◽  
Ningping Wang ◽  
James G. Reeves ◽  
...  
Keyword(s):  
Infarct Size ◽  
Kinase Inhibitor ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Rat Hearts ◽  
Sparing Effect ◽  
Myocardial Ischemia Reperfusion

Protease-activated receptor-2 (PAR-2) may have proinflammatory effects in some tissues and protective effects in other tissues. The role of PAR-2 in in vivo myocardial ischemia-reperfusion has not yet been determined. This study tested the hypothesis that PAR-2 activation with the PAR-2 agonist peptide SLIGRL (PAR-2 AP) reduces myocardial infarct size when given at reperfusion in vivo, and this cardioprotection involves the ERK1/2 pathway. Anesthetized rats were randomly assigned to the following groups with 30 min of regional ischemia and 3 h reperfusion: 1) control with saline; 2) vehicle (DMSO); 3) PAR-2 AP, 1 mg/kg given intravenously 5 min before reperfusion; 4) scrambled peptide (SP), 1 mg/kg; 5) the ERK1/2 inhibitor PD-98059 (PD), 0.3 mg/kg given 10 min before reperfusion; 6) the phosphatidylinositol 3-kinase inhibitor LY-294002 (LY), 0.3 mg/kg given 10 min before reperfusion; 7) PD + PAR-2 AP, 0.3 mg/kg PD given 5 min before PAR-2 AP; 8) LY + PAR-2 AP, 0.3 mg/kg LY given 5 min before PAR-2 AP; 9) chelerythrine (Chel) alone, 5 mg/kg given 10 min before reperfusion; and 10) Chel + PAR-2 AP, Chel was given 5 min before PAR-2 AP (10 min before reperfusion). Activation of ERK1/2, ERK5, Akt, and the downstream targets of ERK1/2 [P90 RSK and bcl-xl/bcl-2-associated death promoter (BAD)] was determined by Western blot analysis in separate experiments. PAR-2 AP significantly reduced infarct size compared with control (36 ± 2% vs. 53 ± 1%, P < 0.05), and SP had no effect on infarct size (53 ± 3%). PAR-2 AP significantly increased phosphorylation of ERK1/2, p90RSK, and BAD but not Akt or ERK5. Accordingly, the infarct-size sparing effect of PAR-2 AP was abolished by PD (PAR-2 AP, 36 ± 2% vs. PD + PAR-2 AP, 50 ± 1%; P < 0.05) and by Chel (Chel + PAR-2 AP, 58 ± 2%) but not by LY (PAR-2 AP, 36 ± 2% vs. LY + PAR-2 AP, 38 ± 3%; P > 0.05). Therefore, PAR-2 activation is cardioprotective in the in vivo rat heart ischemia-reperfusion model, and this protection involves the ERK1/2 pathway and PKC.

scholarly journals Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

2002 ◽  
Vol 97 (6) ◽  
pp. 1485-1490 ◽  
Author(s):  
Katsuya Tanaka ◽  
Dorothee Weihrauch ◽  
Franz Kehl ◽  
Lynda M. Ludwig ◽  
John F. LaDisa ◽  
...  
Keyword(s):  
Infarct Size ◽  
Superoxide Anion ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Oxygen Species ◽  
Superoxide Anion Production ◽  
Anion Production

Background Reactive oxygen species (ROS) contribute to myocardial protection during ischemic preconditioning, but the role of the ROS in protection against ischemic injury produced by volatile anesthetics has only recently been explored. We tested the hypothesis that ROS mediate isoflurane-induced preconditioning in vivo. Methods Pentobarbital-anesthetized rabbits were instrumented for measurement of hemodynamics and were subjected to a 30 min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive vehicle (0.9% saline), or the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptopropionyl glycine (2-MPG; 1 mg. kg(-1).min(-1)), in the presence or absence of 1.0 minimum alveolar concentration (MAC) isoflurane. Isoflurane was administered for 30 min and then discontinued 15 min before coronary artery occlusion. A fluorescent probe for superoxide anion production (dihydroethidium, 2 mg) was administered in the absence of the volatile anesthetic or 5 min before exposure to isoflurane in 2 additional groups (n = 8). Myocardial infarct size and superoxide anion production were assessed using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P &lt; 0.05) decreased infarct size to 24 +/- 4% (mean +/- SEM; n = 10) of the left ventricular area at risk compared with control experiments (43 +/- 3%; n = 8). NAC (43 +/- 3%; n = 7) and 2-MPG (42 +/- 5%; n = 8) abolished this beneficial effect, but had no effect on myocardial infarct size (47 +/- 3%; n = 8 and 46 +/- 3; n = 7, respectively) when administered alone. Isoflurane increased superoxide anion production as compared with control experiments (28 +/- 12 -6 +/- 9 fluorescence units; P &lt; 0.05). Conclusions The results indicate that ROS produced following administration of isoflurane contribute to protection against myocardial infarction in vivo.

Morphine Enhances Pharmacological Preconditioning by Isoflurane

2003 ◽  
Vol 98 (3) ◽  
pp. 705-711 ◽  
Author(s):  
Lynda M. Ludwig ◽  
Hemal H. Patel ◽  
Garrett J. Gross ◽  
Judy R. Kersten ◽  
Paul S. Pagel ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Potassium Channels ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Opioid Receptors ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk

Background Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors. Methods Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane. Results Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane. Conclusions Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.

Preischemic Selenium Status as a Major Determinant of Myocardial Infarct Size In Vivo in Rats

2004 ◽  
Vol 6 (4) ◽  
pp. 792-796 ◽  
Author(s):  
Stéphane Tanguy ◽  
Sandrine Morel ◽  
Corinne Berthonneche ◽  
Marie-Claire Toufektsian ◽  
Michel de Lorgeril ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Major Determinant ◽  
Myocardial Infarct Size ◽  
Selenium Status

scholarly journals Loss of Protein Kinase Novel 1 (PKN1) is associated with mild systolic and diastolic contractile dysfunction, increased phospholamban Thr17 phosphorylation, and exacerbated ischaemia-reperfusion injury

2017 ◽  
Vol 114 (1) ◽  
pp. 138-157 ◽  
Author(s):  
Asvi A Francois ◽  
Kofo Obasanjo-Blackshire ◽  
James E Clark ◽  
Andrii Boguslavskyi ◽  
Mark R Holt ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Infarct Size ◽  
Cell Injury ◽  
Contractile Function ◽  
Myocardial Infarct ◽  
Neonatal Rat ◽  
Myocardial Infarct Size ◽  
Ischaemia Reperfusion ◽  
Sirna Knockdown

Abstract Aims PKN1 is a stress-responsive protein kinase acting downstream of small GTP-binding proteins of the Rho/Rac family. The aim was to determine its role in endogenous cardioprotection. Methods and results Hearts from PKN1 knockout (KO) or wild type (WT) littermate control mice were perfused in Langendorff mode and subjected to global ischaemia and reperfusion (I/R). Myocardial infarct size was doubled in PKN1 KO hearts compared to WT hearts. PKN1 was basally phosphorylated on the activation loop Thr778 PDK1 target site which was unchanged during I/R. However, phosphorylation of p42/p44-MAPK was decreased in KO hearts at baseline and during I/R. In cultured neonatal rat ventricular cardiomyocytes (NRVM) and NRVM transduced with kinase dead (KD) PKN1 K644R mutant subjected to simulated ischaemia/reperfusion (sI/R), PhosTag® gel analysis showed net dephosphorylation of PKN1 during sI and early R despite Thr778 phosphorylation. siRNA knockdown of PKN1 in NRVM significantly decreased cell survival and increased cell injury by sI/R which was reversed by WT- or KD-PKN1 expression. Confocal immunofluorescence analysis of PKN1 in NRVM showed increased localization to the sarcoplasmic reticulum (SR) during sI. GC-MS/MS and immunoblot analysis of PKN1 immunoprecipitates following sI/R confirmed interaction with CamKIIδ. Co-translocation of PKN1 and CamKIIδ to the SR/membrane fraction during sI correlated with phospholamban (PLB) Thr17 phosphorylation. siRNA knockdown of PKN1 in NRVM resulted in increased basal CamKIIδ activation and increased PLB Thr17 phosphorylation only during sI. In vivo PLB Thr17 phosphorylation, Sarco-Endoplasmic Reticulum Ca2+ ATPase (SERCA2) expression and Junctophilin-2 (Jph2) expression were also basally increased in PKN1 KO hearts. Furthermore, in vivo P-V loop analysis of the beat-to-beat relationship between rate of LV pressure development or relaxation and end diastolic P (EDP) showed mild but significant systolic and diastolic dysfunction with preserved ejection fraction in PKN1 KO hearts. Conclusion Loss of PKN1 in vivo significantly reduces endogenous cardioprotection and increases myocardial infarct size following I/R injury. Cardioprotection by PKN1 is associated with reduced CamKIIδ-dependent PLB Thr17 phosphorylation at the SR and therefore may stabilize the coupling of SR Ca2+ handling and contractile function, independent of its kinase activity.

Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury

1998 ◽  
Vol 275 (5) ◽  
pp. H1865-H1872 ◽  
Author(s):  
Anthony J. Palazzo ◽  
Steven P. Jones ◽  
Donald C. Anderson ◽  
D. Neil Granger ◽  
David J. Lefer
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia Reperfusion

We investigated in vivo coronary P-selectin expression and its pathophysiological consequences in a murine model of myocardial ischemia-reperfusion (MI/R) using wild-type and P-selectin deficient (−/−) mice. Coronary P-selectin expression [μg monoclonal antibody (MAb)/g tissue] was measured using a radiolabeled MAb method after 30 min of myocardial ischemia and 20 min of reperfusion. P-selectin expression in wild-type mice was significantly ( P< 0.01) elevated in the ischemic zone (0.070 ± 0.010) compared with the nonischemic zone (0.037 ± 0.008). Myocardial P-selectin expression was nearly undetectable in P-selectin −/− mice after MI/R. Furthermore, myocardial infarct size (% of area at risk) after 30 min of myocardial ischemia and 120 min of reperfusion was 42.5 ± 4.4 in wild-type mice and 24.4 ± 4.0 in P-selectin −/− mice ( P < 0.05). In additional experiments of prolonged myocardial ischemia (60 min) and reperfusion (120 min), myocardial infarct size was similar in P-selectin −/− mice and wild-type mice. Our results clearly demonstrate the involvement of coronary P-selectin in the development of myocardial infarction after MI/R.

Abstract 411: Endogenous miRNA Induced By Ischemic Preconditioning Reduces Myocardial Infarct Size following Ischemia/Reperfusion In Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Chang Yin ◽  
Fadi N Salloum ◽  
Rakesh C Kukreja
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Coronary Artery Ligation ◽  
Myocardial Infarct Size ◽  
Artery Ligation ◽  
Buffer Control

BACKGROUND: Due to its short length (~24 nt) and non-coding nature, microRNA (miRNA) used to be regarded as “evolutionary transcriptional debris”. Recent evidence suggests that miRNA is a novel regulator for transcription and translation. It is known that brief episodes of ischemia during ischemic preconditioning (IPC) trigger complex genetic pro-survival program that results in modulation of several key proteins involved in protection against I/R injury. We hypothesized that miRNA synthesized during IPC is the potential mediator of such protection. METHODS / RESULTS : Hearts were isolated from 3 groups (n = 6/group) of adult ICR mice and subjected to the following treatments in Langendorff mode: 120 min of perfusion with Krebs-Henseleit buffer (control); 30 min global ischemia followed by 1 hr reperfusion (I/R); 2 cycles of 30 sec ischemia and 90 sec reperfusion followed by 30 min ischemia and 1 hr reperfusion (IPC). Infarct size (IS) was measured by triphenyl tetrazolium staining. IPC in the Langendorff model reduced IS from 29.7 ± 2.1% in the I/R hearts to 9.1 ± 1.8 % in the IPC group. This protection was associated with a significant induction of miRNA-1 (162 ± 13%), miRNA-21 (118 ± 6%), and miRNA-24 (46 ± 12%). To test its protective role, miRNA was extracted from 6 hearts following the IPC protocol; and then injected in vivo into the left ventricle wall in another group of 6 mice. Forty-eight hrs later, these mice were subjected to I/R injury in vivo by left coronary artery ligation for 30 min followed by reperfusion for 24 hr. In addition, a subset of mice was treated with miRNA inhibitors (methylated antisense miRNA) in conjunction with miRNA from IPC hearts. The results show that miRNA extracted from the IPC hearts reproduced a protective phenotype with significantly lower infarction (18.8 ± 2.5 %) in vivo as compared to saline-treated control (37.5 ± 2.2%). This protective effect was totally abolished by specific inhibitors of miRNA-1 and miRNA-21 (IS: 43.7 ± 2.1%). CONCLUSION : miRNA extracted from preconditioned hearts shows a protective role against I/R injury. The detection of miRNA in preconditioned hearts offers a novel strategy in cardioprotection. Further studies are needed to identify the gene targets by which miRNA generate protective phenotype.

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