title: Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning.
abstract: BACKGROUND
  Remote ischemic perconditioning (RIPerC) has a promising therapeutic insight to improve the prognosis of acute myocardial infarction. Chronic comorbidities such as diabetes are known to interfere with conditioning interventions by modulating cardioprotective signaling pathways, such as e.g., mTOR pathway and autophagy. However, the effect of acute hyperglycemia on RIPerC has not been studied so far. Therefore, here we investigated the effect of acute hyperglycemia on cardioprotection by RIPerC.
  
  
  METHODS
  Wistar rats were divided into normoglycemic (NG) and acute hyperglycemic (AHG) groups. Acute hyperglycemia was induced by glucose infusion to maintain a serum glucose concentration of 15-20 mM throughout the experimental protocol. NG rats received mannitol infusion of an equal osmolarity. Both groups were subdivided into an ischemic (Isch) and a RIPerC group. Each group underwent reversible occlusion of the left anterior descending coronary artery (LAD) for 40 min in the presence or absence of acute hyperglycemia. After the 10-min LAD occlusion, RIPerC was induced by 3 cycles of 5-min unilateral femoral artery and vein occlusion and 5-min reperfusion. After 120 min of reperfusion, infarct size was measured by triphenyltetrazolium chloride staining. To study underlying signaling mechanisms, hearts were harvested for immunoblotting after 35 min in both the NG and AHG groups.
  
  
  RESULTS
  Infarct size was significantly reduced by RIPerC in NG, but not in the AHG group (NG + Isch: 46.27 ± 5.31 % vs. NG + RIPerC: 24.65 ± 7.45 %, p < 0.05; AHG + Isch: 54.19 ± 4.07 % vs. 52.76 ± 3.80 %). Acute hyperglycemia per se did not influence infarct size, but significantly increased the incidence and duration of arrhythmias. Acute hyperglycemia activated mechanistic target of rapamycine (mTOR) pathway, as it significantly increased the phosphorylation of mTOR and S6 proteins and the phosphorylation of AKT. In spite of a decreased LC3II/LC3I ratio, other markers of autophagy, such as ATG7, ULK1 phopsphorylation, Beclin 1 and SQSTM1/p62, were not modulated by acute hyperglycemia. Furthermore, acute hyperglycemia significantly elevated nitrative stress in the heart (0.87 ± 0.01 vs. 0.50 ± 0.04 µg 3-nitrotyrosine/mg protein, p < 0.05).
  
  
  CONCLUSIONS
  This is the first demonstration that acute hypreglycemia deteriorates cardioprotection by RIPerC. The mechanism of this phenomenon may involve an acute hyperglycemia-induced increase in nitrative stress and activation of the mTOR pathway.
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. baranyai.tamas@med.semmelweis-univ.hu.
authors.forename: Tamás
authors.initials: T
authors.lastname: Baranyai
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. nagy.csilla@med.semmelweis-univ.hu.
authors.forename: Csilla Terézia
authors.initials: CT
authors.lastname: Nagy
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. koncsos.gabor@med.semmelweis-univ.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Koncsos
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. zsofia.onodi@gmail.com.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Onódi
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. karolyi-szabo.melinda@med.semmelweis-univ.hu.
authors.forename: Melinda
authors.initials: M
authors.lastname: Károlyi-Szabó
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. makkosandras@gmail.com.
authors.forename: András
authors.initials: A
authors.lastname: Makkos
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. varga.zoltan@med.semmelweis-univ.hu.
authors.forename: Zoltán V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. peter.ferdinandy@pharmahungary.com.|Pharmahungary Group, Szeged, Hungary. peter.ferdinandy@pharmahungary.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. giricz.zoltan@med.semmelweis-univ.hu.|Pharmahungary Group, Szeged, Hungary. giricz.zoltan@med.semmelweis-univ.hu.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Giricz
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071189:Autophagy-Related Protein-1 Homolog; D000071186:Beclin-1; D006360:Heat-Shock Proteins / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000071456:Sequestosome-1 Protein; D012720:Severity of Illness Index; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C561242:Atg7 protein, rat; D000071186:Beclin-1; C512829:Becn1 protein, rat; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; C002744:3-nitrotyrosine; D014443:Tyrosine; D000071189:Autophagy-Related Protein-1 Homolog; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C586255:ULK1 protein, rat; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes