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.