Abstract
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. 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). 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.
Highlights
Reduction of the burden of ischaemia-reperfusion (I/R) injury is a major challenge of several treatments for cardiovascular diseases
IPost-Co improves cardiac function post-myocardial infarction and reduces reperfusion-induced cell damage by down-regulation of the aryl-hydrocarbon receptor (AhR)-signalling transduction pathway leading to infarct size reduction
1.5 h of ischaemia markedly and diminished left ventricular ejection fraction (LVEF) in all animals visualized by a marked akinesia
Summary
Reduction of the burden of ischaemia-reperfusion (I/R) injury is a major challenge of several treatments for cardiovascular diseases. Emerging data are providing evidence that IPost-Co-triggered cytoplasmic effects mostly converge to inhibit the mitochondrial permeability transition pore (MPTP) in order to partly rescue jeopardized cardiomyocytes.[9,12,13] For instance, IPost-Co has shown to activate via membrane-receptor the pro-survival signal transduction reperfusion injury salvage kinase (RISK)-pathway-preventing MPTP opening limiting irreversible cardiac injury.[14,15] whereas most studies in rodents and isolated ischaemic hearts have clearly demonstrated that infarct size reduction by IPost-Co is RISK dependent, recent studies in pigs have failed to implicate components of the RISK pathway as mediators of IPost-Co protection13,16 – 19 and have supported a causal role for STAT3 (signal transducer and activator of transcription 3) activation in mediating cardioprotection through ameliorating mitochondria function.[20] Such discrepancies have underscored the differences between experimental models (in vivo vs in vitro), species (rodents vs pigs), and/or protocols used (ischaemia severity and duration, IPost-Co algorithms, etc.).[21] More importantly, such observations support the need for further studies in clinically relevant experimental approaches/models to unravel the alterations and signal transduction pathways that may account to the detected cardioprotection afforded by IPost-Co in the clinical scenario.[12,13] As such, a recent study in rats has shown the capability of IPost-Co to reduce the rate of myocyte apoptosis likely via RISK-/mTOR-dependent mechanisms.[22] whether IPost-Co diminishes apoptosis in a humanresembling experimental model remains to be addressed. We have recently reported in pigs that reperfusion is the main trigger of caspase-3 in the setting of I/R.3 On the contrary, IPost-Co has already shown to reduce infarct size, the effect of IPost-Co on cardiac performance and on the mechanisms underlying its protective effects remains largely unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
