Ischemic-Preconditioning Induced Serum Exosomal miR-133a-3p Improved Post-Myocardial Infarction Repair via Targeting LTBP1 and PPP2CA.

Background: Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism. Methods: Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI. Results: IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-ß (TGF-ß) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-ß1in MI rats. Conclusion: IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-ß pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair.

Influence of Anesthetic Regimes on Extracellular Vesicles following Remote Ischemic Preconditioning in Coronary Artery Disease.

Remote ischemic preconditioning (RIPC) reduces ischemia-reperfusion injury in aortocoronary bypass surgery, potentially via extracellular vesicles (EVs) and their micro-RNA content. Clinical data implicate that propofol might inhibit the cardioprotective RIPC effect. This prospective, randomized study investigated the influence of different anesthetic regimes on RIPC efficacy and EV micro-RNA signatures. We also assessed the impact of propofol on cell protection after hypoxic conditioning and EV-mediated RIPC in vitro. H9c2 rat cardiomyoblasts were subjected to hypoxia, with or without propofol, and subsequent simulated ischemia-reperfusion injury. Apoptosis was measured by flow cytometry. Blood samples of 64 patients receiving anesthetic maintenance with propofol or isoflurane, along with RIPC or sham procedures, were analyzed, and EVs were enriched using a polymer-based method. Propofol administration corresponded with increased Troponin T levels (4669 ± 435.6 pg/mL), suggesting an inhibition of the cardioprotective RIPC effect. RIPC leads to a notable rise in miR-21 concentrations in the group receiving propofol anesthesia (fold change 7.22 ± 6.6). In vitro experiments showed that apoptosis reduction was compromised with propofol and only occurred in an EV-enriched preconditioning medium, not in an EV-depleted medium. Our study could clinically and experimentally confirm propofol inhibition of RIPC protection. Increased miR-21 expression could provide evidence for a possible inhibitory mechanism.

Nitric oxide is involved in the cardioprotection of neonatal rat hearts, but not in neonatal ischemic postconditioning.

The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.

Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease.

OBJECTIVE: To test the efficacy of metformin (MET) during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy. BACKGROUND: Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether MET pretreatment could ameliorate therapeutic decrements associated with MS. METHODS: Yorkshire swine (n = 29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg oral MET or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for 5 weeks before the acquisition of functional and perfusion data immediately before terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups. RESULTS: Regardless of EV administration, animals that received MET exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing, improved perfusion to the most ischemic myocardial region at rest and during pacing, and markedly reduced apoptosis. CONCLUSIONS: MET administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and MS.

Vago-splenic signal transduction of cardioprotection in humans.

BACKGROUND AND AIMS: The spleen serves as an important relay organ that releases cardioprotective factor(s) upon vagal activation during remote ischaemic conditioning (RIC) in rats and pigs. The translation of these findings to humans was attempted. METHODS: Remote ischaemic conditioning or electrical auricular tragus stimulation (ATS) were performed in 10 healthy young volunteers, 10 volunteers with splenectomy, and 20 matched controls. Venous blood samples were taken before and after RIC/ATS or placebo, and a plasma dialysate was infused into isolated perfused rat hearts subjected to global ischaemia/reperfusion. RESULTS: Neither left nor right RIC or ATS altered heart rate and heart rate variability in the study cohorts. With the plasma dialysate prepared before RIC or ATS, respectively, infarct size (% ventricular mass) in the recipient rat heart was 36 ± 6% (left RIC), 34 ± 3% (right RIC) or 31 ± 5% (left ATS), 35 ± 5% (right ATS), and decreased with the plasma dialysate from healthy volunteers after RIC or ATS to 20 ± 4% (left RIC), 23 ± 6% (right RIC) or to 19 ± 4% (left ATS), 26 ± 9% (right ATS); infarct size was still reduced with plasma dialysate 4 days after ATS and 9 days after RIC. In a subgroup of six healthy volunteers, such infarct size reduction was abrogated by intravenous atropine. Infarct size reduction by RIC or ATS was also abrogated in 10 volunteers with splenectomy, but not in their 20 matched controls. CONCLUSIONS: In humans, vagal innervation and the spleen as a relay organ are decisive for the cardioprotective signal transduction of RIC and ATS.

Cardioprotection in cardiovascular surgery.

Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.

Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration.

Growth/differentiation factor-15 (GDF15) is considered an unfavourable prognostic biomarker for cardiovascular disease in clinical data, while experimental studies suggest it has cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia-reperfusion injury in Wistar male rats, employing concentrations relevant to patients at high cardiovascular risk. Initially, we examined circulating levels and heart tissue expression of GDF15 in rats subjected to ischemia-reperfusion and sham operations in vivo. We then evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before 30 min of ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct size and cardiac contractile recovery between control and rGDF15-treated rats. Contrary to our expectations, ischemia-reperfusion did not increase GDF15 plasma levels compared to sham-operated rats. However, cardiac protein and mRNA expression increased in the infarcted zone of the ischemic heart after 24 h of reperfusion. Notably, preconditioning with rGDF15 had a cardioprotective effect, reducing infarct size both in vivo (65 ± 5% in control vs. 42 ± 6% in rGDF15 groups) and ex vivo (60 ± 4% in control vs. 45 ± 4% in rGDF15 groups), while enhancing cardiac contractile recovery ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters in vivo or ex vivo. These novel findings reveal that the short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against ischemia-reperfusion injury in both in vivo and ex vivo settings. The ex vivo results indicate that rGDF15 operates independently of the inflammatory, endocrine and nervous systems, suggesting direct and potent cardioprotective properties against ischemia-reperfusion injury.

Inhibition of the protective effects of preconditioning in ischemia-reperfusion injury by chronic methadone: the role of pAkt and pSTAT3.

Cardiac ischemic preconditioning (Pre) reduces cardiac ischemia-reperfusion injury (IRI) by stimulating opioid receptors. Chronic use of opioids can alter the signaling pathways. We investigated the effects of chronic methadone use on IRI and Pre. The experiments were performed on isolated hearts of male Wistar rats in four groups: IRI, Methadone + IRI (M-IRI), Pre + IRI (Pre-IRI), Methadone + Pre + IRI (M-Pre-IRI). The infarct size (IS) in the Pre-IRI group was smaller than the IRI group (26.8% vs. 47.8%, P < 0.05). In the M-IRI and M-Pre-IRI groups, the infarct size was similar to the IRI group. Akt (Ak strain transforming) phosphorylation in the Pre-IRI, M-IRI, and M-Pre-IRI groups was significantly higher than in the IRI group (0.56 ± 0.15, 0.63 ± 0.20, and 0.93 ± 0.18 vs 0.28 ± 0.17 respectively). STAT3 (signal transducer and activator of transcription 3) phosphorylation in the Pre-IRI and M-Pre-IRI groups (1.38 ± 0.14 and 1.46 ± 0.33) was significantly higher than the IRI and M-IRI groups (0.99 ± 0.1 and 0.98 ± 0.2). Thus, chronic use of methadone not only has no protective effect against IRI but also destroys the protective effects of ischemic preconditioning. This may be due to the hyperactivation of Akt and changes in signaling pathways.

Is There a Mitochondrial Protection via Remote Ischemic Conditioning in Settings of Anticancer Therapy Cardiotoxicity?

PURPOSE OF REVIEW: To provide an overview of (a) protective effects on mitochondria induced by remote ischemic conditioning (RIC) and (b) mitochondrial damage caused by anticancer therapy. We then discuss the available results of studies on mitochondrial protection via RIC in anticancer therapy-induced cardiotoxicity. RECENT FINDINGS: In three experimental studies in healthy mice and pigs, there was a RIC-mediated protection against anthracycline-induced cardiotoxicity and there was some evidence of improved mitochondrial function with RIC. The RIC-mediated protection was not confirmed in the two available studies in cancer patients. In adult cancer patients, RIC was associated with an adverse outcome. There are no data on mitochondrial function in cancer patients. Studies in tumor-bearing animals are needed to determine whether RIC does not interfere with the anticancer properties of the drugs and whether RIC actually improves mitochondrial function, ultimately resulting in improved cardiac function.

Effects of Remote Ischaemic Conditioning in Stable and Unstable Angina Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

AIM: Type 4a myocardial infarction (T4aMI), defined as myocardial injury associated with percutaneous coronary intervention (PCI), is associated with a poor prognosis and there is conflicting evidence regarding the effectiveness of remote ischaemic conditioning (RIC) in its prevention. This review aimed to determine the effect of RIC on stable and unstable angina patients. METHOD: A systematic review was conducted in PubMed and Central database. Outcome measures were: changes in peak troponin, creatine kinase myocardial band (CKMB), C-reactive protein (CRP) level, incidence of T4aMI, and major adverse cardiovascular event (MACE). Data were meta-analysed and reported as standardised mean difference (SMD) and odds ratio (OR). Risk of bias was assessed with the Risk of Bias 2 (RoB2) tool. RESULTS: Fifteen studies with no significant risk of bias were included. Peak troponin level was reduced in the RIC group, particularly after excluding a study with low statin use, while CKMB and CRP levels resulted in a non-significant SMD between the groups. The incidence of T4aMI was significantly lower in the intervention group (OR 0.714; p=0.026); this finding was also seen in subgroups of elective PCI, pre-conditioning, and high statin use. Incidence of MACE also only reached statistically significant protective effects with OR <1 in similar subgroups. No substantial heterogeneity was found and the funnel plot did not show publication bias. CONCLUSION: Remote ischaemic conditioning in elective PCI patients has been proven to be potentially beneficial in reducing peak troponin levels and risk of T4aMI and MACE.

Precondicionamiento isquémico remoto: bases de la protección y resultados clínicos / Remote ischemic preconditioning: Bases and clinical results

El precondicionamiento isquémico remoto es una manera eficaz de disminuir el daño por isquemia y reperfusión en el corazón y otros órganos como cerebro o riñón, en modelos experimentales. Este consiste en realizar entre 3 y 5 ciclos de 5 minutos de isquemia seguidos del mismo tiempo de reperfusión, en un tejido alejado del que se quiere proteger, normalmente una extremidad. Estudios preclínicos en animales indican que la isquemia precondicionante inicia señales nerviosas y humorales en el tejido isquémico remoto, que en el corazón activan mecanismos de protección. La señal nerviosa se origina en fibras sensoriales que a nivel cerebral producen una activación del sistema parasimpático. El nervio vago activa ganglios cardíacos intrínsecos del corazón lo que induce protección. Además, desde el tejido isquémico se liberan a la circulación diferentes mediadores que viajan en forma libre o en vesículas lipídicas (exosomas) que inician vías de señalización protectoras en el corazón. A pesar del éxito del precondicionamiento isquémico remoto en animales de experimentación, su aplicación en seres humanos no ha tenido resultados claros. Esta discrepancia puede deberse a una diversidad de factores tales como la edad, la existencia de otras patologías, uso de fármacos u otros tratamientos que afectan la respuesta de los pacientes. Se requiere un mayor conocimiento de las bases moleculares de este mecanismo de protección para que su aplicación en clínica sea exitosa.

In experimental models, remote ischemic preconditioning effectively decreases ischemia reperfusion injury to the heart and other organs such as the brain or kidney. It consists of 3 to 5 cycles of 5 minutes of ischemia followed by 5 minutes of reperfusion, in a remote tissue, usually a limb. Preclinical studies in animals indicate that preconditioning ischemia initiates neural and humoral signals in the remote ischemic tissue, which activate protective mechanisms in the heart. The nervous signal originates in sensory fibers that activate the parasympathetic system in the brain. The vagus nerve activates the intrinsic cardiac ganglia of the heart, leading to protection from ischemic injury. Furthermore, mediators are released from the ischemic tissue into the circulation that travels freely or in lipid vesicles (exosomes) to the heart where they initiate protective signaling pathways. Despite the success of remote ischemic preconditioning in experimental animals, its application in humans has not produced clear results. This discrepancy may be due to a variety of factors such as age, the existence of other pathologic processes, or the use of drugs or other treatments that affect the patient´s response. An increased knowledge of the molecular bases of this protective mechanism is required for its clinical application to be successful.

Is Intrinsic Cardioprotection a Laboratory Phenomenon or a Clinically Relevant Tool to Salvage the Failing Heart?

Cardiovascular diseases, especially ischemic heart disease, as a leading cause of heart failure (HF) and mortality, will not reduce over the coming decades despite the progress in pharmacotherapy, interventional cardiology, and surgery. Although patients surviving acute myocardial infarction live longer, alteration of heart function will later lead to HF. Its rising incidence represents a danger, especially among the elderly, with data showing more unfavorable results among females than among males. Experiments revealed an infarct-sparing effect of ischemic "preconditioning" (IPC) as the most robust form of innate cardioprotection based on the heart's adaptation to moderate stress, increasing its resistance to severe insults. However, translation to clinical practice is limited by technical requirements and limited time. Novel forms of adaptive interventions, such as "remote" IPC, have already been applied in patients, albeit with different effectiveness. Cardiac ischemic tolerance can also be increased by other noninvasive approaches, such as adaptation to hypoxia- or exercise-induced preconditioning. Although their molecular mechanisms are not yet fully understood, some noninvasive modalities appear to be promising novel strategies for fighting HF through targeting its numerous mechanisms. In this review, we will discuss the molecular mechanisms of heart injury and repair, as well as interventions that have potential to be used in the treatment of patients.

p55γ degrades RIP3 via MG53 to suppress ischaemia-induced myocardial necroptosis and mediates cardioprotection of preconditioning.

AIMS: Regulated necrosis (necroptosis) and apoptosis are important biological features of myocardial infarction, ischaemia-reperfusion (I/R) injury, and heart failure. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Ischaemic preconditioning (IPC) is the most powerful intrinsic cardioprotection against myocardial I/R injury. In this study, we aimed to determine whether IPC suppresses I/R-induced necroptosis and the underlying molecular mechanisms. METHODS AND RESULTS: We generated p55γ transgenic and knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of p55γ and its downstream molecules were subsequently identified using mass spectroscopy and co-immunoprecipitation and pulldown assays. We found that p55γ expression was down-regulated in failing human myocardium caused by coronary heart disease as well as in I/R mouse hearts. Cardiac-specific p55γ overexpression ameliorated the I/R-induced necroptosis. In striking contrast, p55γ deficiency (p55γ-/-) and cardiac-specific deletion of p55γ (p55γc-KO) worsened I/R-induced injury. IPC up-regulated p55γ expression in vitro and in vivo. Using reporter and chromatin immunoprecipitation assays, we found that Hif1α transcriptionally regulated p55γ expression and mediated the cardioprotection of IPC. IPC-mediated suppression of necroptosis was attenuated in p55γ-/- and p55γc-KO hearts. Mechanistically, p55γ overexpression decreased the protein levels of RIP3 rather than the mRNA levels, while p55γ deficiency increased the protein abundance of RIP3. IPC attenuated the I/R-induced up-regulation of RIP3, which was abolished in p55γ-deficient mice. Up-regulation of RIP3 attenuated the p55γ- or IPC-induced inhibition of necroptosis in vivo. Importantly, p55γ directly bound and degraded RIP3 in a ubiquitin-dependent manner. We identified MG53 as the E3 ligase that mediated the p55γ-induced degradation of RIP3. In addition, we also found that p55γ activated the RISK pathway during IPC. CONCLUSIONS: Our findings reveal that activation of the MG53-RIP3 signal pathway by p55γ protects the heart against I/R-induced necroptosis and underlies IPC-induced cardioprotection.

Effects of remote ischaemic preconditioning on myocardial injury after major abdominal surgery in patients at high risk for cardiovascular adverse events in China (RIPC-MAS): protocol for a randomised, sham-controlled, observer-blinded trial.

INTRODUCTION: Myocardial injury after non-cardiac surgery (MINS) caused by an ischaemic mechanism is common and is associated with adverse short-term and long-term prognoses. However, MINS is a recent concept, and few studies have prospectively used it as a primary outcome. Remote ischaemic preconditioning (RIPC) is a non-invasive procedure that induces innate cardioprotection and may reduce MINS. METHODS AND ANALYSIS: This is a multicentre, randomised, sham-controlled, observer-blinded trial. Patients with a high clinical risk of cardiovascular events who are scheduled to undergo major abdominal surgery will be enrolled. A total of 766 participants will be randomised (1:1 ratio) to receive RIPC or control treatment before anaesthesia. RIPC will comprise four cycles of cuff inflation for 5 min to 200 mm Hg and deflation for 5 min. In the controls, an identical-looking cuff will be placed around the arm but will not be actually inflated. The primary outcome will be MINS, defined as at least one postoperative cardiac troponin (cTn) concentration above the 99th percentile upper reference limit of the cTn assay as a result of a presumed ischaemic mechanism. This trial will test the concentration of high-sensitivity cardiac troponin T (hs-cTnT). The secondary outcomes will be hs-cTnT levels reaching/above the prognostically important thresholds, peak hs-cTnT and total hs-cTnT release during the initial 3 days after surgery, length of hospital stay after surgery, length of stay in the intensive care unit, myocardial infarction, major adverse cardiovascular events, cardiac-related death, all-cause death within 30 days, 6 months, 1 year and 2 years after surgery, and postoperative complications and adverse events within 30 days after surgery. ETHICS AND DISSEMINATION: This study protocol (version 5.0 on 7 April 2023) was approved by the Ethics Committee of Sixth Affiliated Hospital of Sun Yat-sen University. The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05733208.

Endless Journey of Adenosine Signaling in Cardioprotective Mechanism of Conditioning Techniques: Clinical Evidence.

Myocardial ischemic injury is a primary cause of death among various cardiovascular disorders. The condition occurs due to an interrupted supply of blood and vital nutrients (necessary for normal cellular activities and viability) to the myocardium, eventually leading to damage. Restoration of blood supply to ischemic tissue is noted to cause even more lethal reperfusion injury. Various strategies, including some conditioning techniques, like preconditioning and postconditioning, have been developed to check the detrimental effects of reperfusion injury. Many endogenous substances have been proposed to act as initiators, mediators, and end effectors of these conditioning techniques. Substances, like adenosine, bradykinin, acetylcholine, angiotensin, norepinephrine, opioids, etc., have been reported to mediate cardioprotective activity. Among these agents, adenosine has been widely studied and suggested to have the most pronounced cardioprotective effects. The current review article highlights the role of adenosine signaling in the cardioprotective mechanism of conditioning techniques. The article also provides an insight into various clinical studies that substantiate the applicability of adenosine as a cardioprotective agent in myocardial reperfusion injury.

Attenuation of ST-segment elevation by ischemic preconditioning: Reflection of cardioprotection in Göttingen but not in Ossabaw minipigs.

BACKGROUND: Ischemic preconditioning (IPC; brief cycles of coronary occlusion/ reperfusion) reduces myocardial infarct size. The ST-segment elevation during coronary occlusion is progressively attenuated with increasing number of IPC cycles. Progressive attenuation of ST-segment elevation is considered a result of sarcolemmal KATP channel activation and has been considered to reflect and predict IPC's cardioprotection. We have recently demonstrated that IPC failed to reduce infarct size in minipigs of a particular strain (Ossabaw), which had a genetic predisposition to develop, but not yet established a metabolic syndrome. To determine whether or not Ossabaw minipigs nevertheless had attenuated ST-segment elevation over repetitive IPC cycles, we compared Göttingen vs. Ossabaw minipigs in which IPC reduces infarct size. METHODS AND RESULTS: We analyzed surface chest electrocardiographic (ECG) recordings of anesthetized open-chest contemporary Göttingen (n = 43) and Ossabaw minipigs (n = 53). Both minipig strains were subjected to 60 min coronary occlusion and 180 min reperfusion without or with IPC (3 × 5 min/ 10 min coronary occlusion/ reperfusion). ST-segment elevations during the repetitive coronary occlusions were analyzed. In both minipig strains, IPC attenuated ST-segment elevation with increasing number of coronary occlusions. IPC reduced infarct size in Göttingen minipigs (45 ± 10% without vs. 25 ± 13% of area at risk with IPC), whereas such cardioprotection was absent in Ossabaw minipigs (54 ± 11% vs. 50 ± 11%). CONCLUSION: Apparently, the block of signal transduction of IPC in Ossabaw minipigs occurs distal to the sarcolemma, where KATP channel activation still attenuates ST-segment elevation as it does in Göttingen minipigs.

Hydrogen peroxide preconditioning is of dual role in cardiac ischemia/reperfusion.

Moderate reactive oxygen species (ROS) at reperfusion would trigger cardioprotection and various antioxidants for pharmacological preconditioning failed to achieve cardioprotection. The causes for different roles of preischemic ROS during cardiac ischemia/reperfusion (I/R) require reevaluation. We investigated the precise role of ROS and its working model in this study. Different doses of hydrogen peroxide (H2O2, the most stable form of ROS) were added 5 min before ischemia using isolated perfused rat hearts, only moderate-dose H2O2 preconditioning (H2O2PC) achieved contractile recovery, whereas the low dose and high dose led to injury. Similar results were observed in isolated rat cardiomyocytes on cytosolic free Ca2+ concentration ([Ca2+]c) overload, ROS production, the recovery of Ca2+ transient, and cell shortening. Based on the data mentioned above, we set up a mathematics model to describe the effects of H2O2PC with the fitting curve by the percentage of recovery of heart function and Ca2+ transient in I/R. Besides, we used the two models to define the initial thresholds of H2O2PC achieving cardioprotection. We also detected the expression of redox enzymes and Ca2+ signaling toolkits to explain the mathematics models of H2O2PC in a biological way. The expression of tyrosine 705 phosphorylation of STAT3, Nuclear factor E2-related factor 2, manganese superoxide dismutase, phospholamban, catalase, ryanodine receptors, and sarcoendoplasmic reticulum calcium ATPase 2 were similar with the control I/R and low-dose H2O2PC but were increased in the moderate H2O2PC and decreased in the high-dose H2O2PC. Thus, we concluded that preischemic ROS are of dual role in cardiac I/R.

Exosomes as perioperative therapeutics to limit organ injury.

Perioperative organ injury is a frequent and major complication for the ∼240 million people undergoing surgery worldwide annually. Ischaemic preconditioning is a powerful technique that reduces organ injury in experimental models of heart, lung, gut, brain, and kidney ischaemia-reperfusion injury. However, ischaemic preconditioning has been a challenge to translate into clinical practice. We describe how utilising isolated pre-conditioned exosomes (secreted vesicles containing many cell-survival mediators), some of the translational hurdles of ischaemic preconditioning can be overcome. Delivery of exosomes in the perioperative period could become a promising new therapeutic strategy to prevent perioperative organ injury.