Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway.
AIMS
Ischaemic post-conditioning (IPost-Co) exerts cardioprotection by diminishing ischaemia/reperfusion injury. Yet, the mechanisms involved in such protection remain largely unknown. We have investigated the effects of IPost-Co in cardiac cells and in heart performance using molecular, proteomic and functional approaches.


METHODS AND RESULTS
Pigs underwent 1.5 h mid-left anterior descending balloon occlusion and then were sacrificed without reperfusion (ischaemia; n= 7), subjected to 2.5 h of cardiac reperfusion and sacrificed (n= 5); or subjected to IPost-Co before reperfusion and sacrificed 0.5 h (n= 4) and 2.5 h (n= 5) afterwards. A sham-operated group was included (n= 4). Ischaemic and non-ischaemic myocardium was obtained for molecular/histological analysis. Proteomic analysis was performed by two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization-time-of-flight identification. Potential protein networks involved were identified by bioinformatics and Ingenuity Pathway Analysis (IPA). Cardiac function was assessed by echocardiography. IPost-Co diminished (up to 2.5 h) reperfusion-induced apoptosis of both the intrinsic and extrinsic pathways whereas it did not affect reperfusion-induced Akt/mammalian target of rapamycin (mTOR)/P70S6K activation. Proteomic studies showed that IPost-Co reverted 43% of cardiac cytoplasmic protein changes observed during ischaemia and ischaemia + reperfusion. Systems biology assessment revealed significant changes in the aryl-hydrocarbon receptor (AhR) pathway (cell damage related). Bioinformatic data were confirmed since the expression of HSP90, AhR, ANRT, and β-tubulin (involved in AhR-signalling transduction) were accordingly modified after IPost-Co. IPost-Co rescued 52% of the left ventricle-at-risk compared with reperfusion alone and resulted in a ≈30% relative improvement in left ventricular ejection fraction (P <0.05).


CONCLUSION
IPost-Co improves cardiac function post-myocardial infarction and reduces reperfusion-induced cell damage by down-regulation of the AhR-signalling transduction pathway ultimately leading to infarct size reduction.
['Vilahur|Gemma|G|', 'Cubedo|Judit|J|', 'Casani|Laura|L|', 'Padro|Teresa|T|', 'Sabate-Tenas|Manel|M|', 'Badimon|Juan J|JJ|', 'Badimon|Lina|L|']
D000818:Animals D017209:Apoptosis D051784:Aryl Hydrocarbon Receptor Nuclear Translocator D053181:Caspase 8 D003331:Coronary Vessels D003856:Deoxyuracil Nucleotides D004452:Echocardiography D006360:Heat-Shock Proteins D057775:Ischemic Postconditioning D009200:Myocardial Contraction D015428:Myocardial Reperfusion Injury D019869:Phosphatidylinositol 3-Kinases D020543:Proteome D040901:Proteomics D019253:Proto-Oncogene Proteins c-bcl-2 D011897:Random Allocation D018336:Receptors, Aryl Hydrocarbon D015398:Signal Transduction D034421:Sus scrofa D049490:Systems Biology D058570:TOR Serine-Threonine Kinases
Ischaemic post-conditioning Proteomics Cell damage AhR pathway