Targeting the molecular mechanisms of ischemic damage: Protective effects of alpha-crystallin-B

•Changes in cryab myocardial distribution in ischemia, reperfusion and IPost-Co•Administration of cryab monomer exerts a cardioprotective effect against ischemia.•Cryab oligomerization upon ischemia previous to its secretion from the myocardium•Active release of cryab oligomers from the ischemic myocardium during reperfusion

AimsMolecular chaperones constitute protectors of intracellular protein integrity and seem to confer short-term defence against various cell insults. Myocardial damage is associated to a loss of protective chaperones. Ischemic post-conditioning (IPost-Co) is a procedure that seems to protect against reperfusion injury. However, little is known on alpha-crystallin-B-chain (cryab/HspB5) evolution in IPost-Co. Here we have investigated cryab in myocardial ischemia and IPost-Co.Methods and resultsPigs underwent closed-chest 1.5 h mid-left anterior descending (LAD) balloon occlusion and were either sacrificed without reperfusion (I;N = 10), subjected to 2.5 h of reperfusion and sacrificed (I/R; N = 5); or subjected to IPost-Co before reperfusion and sacrificed 2.5 h afterwards (IPost-Co; N = 5). A sham-operated group was included (N = 6). Proteomic analysis (2-D-electrophoresis/MALDI-TOF/TOF) revealed cryab as a single spot (20 kDa; pI7.6). Myocardial cryab-20-protein and cryab-gene expression levels were decreased after ischemia and I/R(P < 0.05). After IPost-Co, cryab-20-protein and cryab-gene expression levels were similar to those found in the heart of sham-operated animals (P < 0.05). There was a direct correlation between LVEF-improvement after IPost-Co and myocardial cryab-20-protein levels. In a mice proof-of-principle study, cryab-20-peptide was synthesized and administered 1 h before LAD-ligation and ECG-proven MI. A 59% reduction in infarct size was achieved in cryab-20-treated animals (P < 0.05).ConclusionsIschemia and reperfusion induce a decrease in myocardial cryab-20-protein levels together with a clinical impairment of cardiac function. IPost-Co induces a clinical improvement of cardiac function and a preservation of cryab-20 levels. Intervention studies on a mice-MI model showed that cryab-20-peptide administration reduces infarct size. All together our results show a significant cardioprotective effect of cryab.