Preconditioning effects of steroids and hyperoxia on cardiac ischemia-reperfusion injury and vascular reactivity

doi:10.1016/j.ejcts.2007.12.017

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Preconditioning effects of steroids and hyperoxia on cardiac ischemia–reperfusion injury and vascular reactivity

Mari-Liis Kaljusto^a^,b^,_*, Kåre-Olav Stensløkken^b^,c, Tomohisa Mori^b^,1, Andrey Panchenko^b^,2, Marthe-Lise Frantzen^b^,c, Guro Valen^d, Jarle Vaage^b^,c

^a Department of Cardiothoracic Surgery, Faculty Division Ullevål University Hospital, Oslo, Norway
^b Institute of Experimental Medical Research, Ullevål University Hospital, Oslo, Norway
^c Department of Surgery, Faculty Division Ullevål University Hospital, Oslo, Norway
^d Institute of Basic Medical Science, Department of Physiology, University of Oslo, Oslo, Norway

Received 19 September 2007; received in revised form 4 December 2007; accepted 10 December 2007.

^_* Corresponding author. Address: Department of Cardiothoracic Surgery, Ullevål University Hospital, 0407 Oslo, Norway. Tel.: +47 99727991; fax: +47 23015881. (Email: m.l.kaljusto{at}medisin.uio.no).

Objective: Corticosteroids and hyperoxia protect the heart againstischemia–reperfusion injury and may attenuate vascularreactivity. We hypothesized that (1) combining these two pretreatmentsinduces an additive cardioprotection, (2) protection dependson activation of survival kinases and/or heat shock proteins,and (3) these interventions would change vascular reactivityinto a more relaxed state. Methods: Male rats were randomized(n = 10 in each group): 1. control, 2. dexamethasone (3 mg/kg)injected 24 and 12 h before harvesting the hearts, 3. 60 minof hyperoxia (90–95% O₂) immediately before harvest, 4.combination of dexamethasone and hyperoxia as in groups 2 and3. The hearts were Langendorff-perfused and exposed to 30 minof global ischemia and reperfused for 120 min. Cardiac functionwas monitored and infarct size determined. Isometric tensionto vasoconstrictive and vasodilatory agents was measured infemoral artery rings. Phosphorylation of survival kinases (proteinkinase B/AKT, extracellular signal-regulated kinases (ERK1/2),the stress-activated/c-Jun NH2 terminal kinases (SAPK/JNK) andp38 MAPK), adenosine monophosphate dependent kinase (AMPK) andexpression of heat shock protein 72 (HSP72) in hearts was evaluatedby immunoblotting. Results: Infarct size was attenuated in allpretreated groups versus controls: 29% reduction in the combinedgroup (p < 0.01), 23% in hyperoxia group (p < 0.05)and 31% in dexamethasone group (p < 0.01). There was nosignificant difference between the treated groups. Combinedpretreatment improved postischemic left ventricular end diastolicpressure compared to all other groups (p < 0.001 vs controls,p = 0.002 vs dexamethasone, p = 0.005 vs hyperoxia). Combinedpretreatment improved left ventricular developed pressure andcoronary flow compared to controls (p < 0.001 for both)and hyperoxia (p = 0.0047 and p = 0.0024, respectively). Combinedpretreatment enhanced endothelium-independent relaxation (p = 0.0032) compared to controls. Excepting ERK1/2 phosphorylationin the combined group during early reperfusion, there was noincreased phosphorylation of the survival kinases AKT, p38,JNK, or AMPK and no increase of HSP72 expression. Conclusion:Combined pretreatment by hyperoxia and dexamethasone improvedpostischemic heart function, but did not reduce infarct sizecompared to single pretreatment groups. Except of a possiblerole of ERK1/2, protection depended neither on survival kinasesnor heat shock protein 72.

Key Words: Preconditioning • Steroids • Hyperoxia • Ischemia–reperfusion injury