title: Transient carotid ischemia as a remote conditioning stimulus for myocardial protection in anesthetized rabbits: Insights into intracellular signaling.
abstract: BACKGROUND
  We investigated the effectiveness of perconditioning (Perc) applied at different time points along with the role of RISK, SAFE, STAT5 and eNOS pathways.
  
  
  RESULTS
  Anesthetized rabbits were subjected to 30-min ischemia/3-hour reperfusion. Perc, consisted of 4 cycles of 1-min ischemia/reperfusion, was applied in the carotid artery at different time points. Perc was started and ended during ischemia, started during ischemia and ended at the beginning of reperfusion, started at the end of ischemia and ended at reperfusion and started and ended during reperfusion. The PI3K inhibitor wortmannin, or the JAK-2 inhibitor AG490, was also applied and the infarct size was assessed. In another series assigned to the previous groups, the phosphorylation of Akt, PI3K, ERKs1/2, GSK3β, STAT3, and STAT5 was evaluated. All Perc groups had smaller infarction compared to those without Perc, independently of PI3K or JAK-2 inhibition. STAT5 was the only molecule that was phosphorylated in parallel with cardioprotection. Since Src and angiotensin II mediate the STAT5 pathway, we administered the Scr inhibitor PP1 and the angiotensin II receptor antagonist valsartan. PP1 and valsartan prevented STAT5 phosphorylation, but did not abrogate the effect of Perc. Furthermore, the NOS inhibitor L-NAME was administered and abrogated the infarct size limiting effect of Perc. In parallel, the expression of cleaved caspase-3 was elevated only in the control and Perc-A-L-NAME groups.
  
  
  CONCLUSIONS
  Perc reduces infarction independently of RISK, SAFE and STAT5 pathways. Src kinase and angiotensin II play a predominant role in STAT5 activation. eNOS may protect the myocardium through inhibition of apoptosis.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece. Electronic address: jandread@pharm.uoa.gr.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
authors.affiliation: Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
authors.forename: Sofia-Iris
authors.initials: SI
authors.lastname: Bibli
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mastromanolis
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zoga
authors.affiliation: Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Efentakis
authors.affiliation: Department of Pathology, School of Health Sciences, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papaioannou
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Farmakis
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Dimitrios Th
authors.initials: DT
authors.lastname: Kremastinos
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Efstathios K
authors.initials: EK
authors.lastname: Iliodromitis
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D007424:Intracellular Fluid / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*
keywords: Cardioprotection; Perconditioning; RISK; SAFE; STAT5; eNOS