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Myocardial ischemia‐reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK‐MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex‐treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI. Dex reduces lactate levels and downregulates MDH2 lactylation to enhance mitochondrial function and prevent ferroptosis, ultimately alleviating myocardial ischemia‐reperfusion injury. This mechanism involves through Dex facilitating the phosphorylation and nuclear export of NR3C1, leading to the suppression of PDK4 and influencing metabolic reprogramming.

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.

Purpose: To report a randomized clinical trial designed to determine if remote ischemic preconditioning (IP) has the ability to reduce renal and cardiac damage following endovascular aneurysm repair (EVAR). Methods: Forty patients (all men; mean age 76±7 years) with abdominal aortic aneurysms averaging 6.3±0.8 cm in diameter were enrolled in the trial from November 2006 to January 2008. Eighteen patients (mean age 74 years, range 72–81) were randomized to preconditioning and completed the full remote IP protocol; there were no withdrawals. Twenty-two patients (mean age 76 years, range 66–80) were assigned to the control group. Remote IP was induced using sequential lower limb ischemia. Serum and urinary markers of renal and cardiac injury were compared between the groups. Results: Urinary retinol binding protein (RBP) levels increased 10-fold from a median of 235 µmol/L to 2356 µmol/L at 24 hours (p=0.0001). There was a lower increase in the preconditioned group, from 167 µmol/L to 413 µmol/L at 24 hours (p=0.04). The median urinary albumin:creatinine ratio was significantly lower in the preconditioned group at 24 hours (5 versus 8.8, p=0.06). There were no differences in the rates of renal impairment or major adverse cardiac events. Conclusion: Remote preconditioning reduces urinary biomarkers of renal injury in patients undergoing elective EVAR. This small pilot trial was unable to detect an effect on clinical endpoints; further trials are warranted.

Ischemia–reperfusion injury remains a major challenge in free flap surgery, contributing to oxidative stress, inflammation, and cell death that impair tissue viability and outcomes. Remote ischemic preconditioning (RIPC) has emerged as a potential protective strategy by modulating cellular stress responses, but its molecular mechanisms in free flaps remain incompletely understood. We prospectively enrolled 36 female patients undergoing autologous breast reconstruction with mainly deep inferior epigastric perforator (DIEP) free flaps, randomised into three groups: No RIPC, Early RIPC (24 h preconditioning), and Late RIPC (1 h preconditioning). Tissue samples were collected pre‐ischemia and post‐reperfusion for immunohistochemical and multiplex protein analyses. RIPC did not reduce oxidative stress markers, as 4‐hydroxynonenal (4‐HNE) levels were comparable across groups, while 3‐nitrotyrosine levels paradoxically increased after RIPC. Early RIPC selectively modulated cell death pathways, with decreased expression of mitochondrial apoptotic marker caspase 9 and reduced necroptotic activation of mixed lineage kinase domain‐like protein (MLKL) after reperfusion. Caspase 8 showed a transient modulation, suggesting effects on apoptosis‐necroptosis crosstalk. Cyclophilin A levels were elevated after reperfusion in RIPC groups, indicating an adaptive stress response. These findings suggest that early RIPC exerts selective protection by modulating apoptosis and necroptosis, rather than broadly reducing oxidative stress. RIPC may represent a targeted strategy to improve free flap survival in reconstructive surgery.

Key Points Currently, no treatment has been proven to be effective for preventing 'myocardial reperfusion injury' — the death of cardiomyocytes that paradoxically occurs when reperfusing ischaemic myocardium One or more brief cycles of ischaemia and reperfusion can protect the heart from acute myocardial infarction and myocardial reperfusion injury — a phenomenon termed 'ischaemic conditioning' Ischaemic conditioning can be applied either directly to the heart or from afar; that is, to a remote organ or tissue (such as an arm or a leg) Investigation of signalling pathways underlying ischaemic conditioning has identified molecular targets for pharmacological manipulation — a therapeutic strategy termed 'pharmacological cardioprotection' Proof-of-concept clinical studies have shown mixed results of ischaemic conditioning in cardiac surgery and percutaneous coronary intervention; more consistently positive results have been observed in acute myocardial infarction The results of large, multicentre, randomized, controlled clinical trials of ischaemic conditioning on clinical outcomes after cardiac surgery have highlighted the challenges in translating cardioprotection into clinical practice Ischaemic conditioning is an endogenous cardioprotective strategy that involves the application of brief cycles of ischaemia and reperfusion either directly to the heart, or to a remote organ or tissue, and which has been shown to reduce infarct size. In this Review, Hausenloy and Yellon summarize the various forms of ischaemic conditioning and pharmacological cardioprotection, and highlight the challenges of translating these methods into the clinical setting. The 30-year anniversary of the discovery of 'ischaemic preconditioning' is in 2016. This endogenous phenomenon can paradoxically protect the heart from acute myocardial infarction by subjecting it to one or more brief cycles of ischaemia and reperfusion. Apart from complete reperfusion, this method is the most powerful intervention known for reducing infarct size. The concept of ischaemic preconditioning has evolved into 'ischaemic conditioning', a term that encompasses a number of related endogenous cardioprotective strategies, applied either directly to the heart (ischaemic preconditioning or postconditioning) or from afar, for example a limb (remote ischaemic preconditioning, perconditioning, or postconditioning). Investigations of signalling pathways underlying ischaemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. Over the past 3 decades, a number of ischaemic and pharmacological cardioprotection strategies, discovered in experimental studies, have been examined in the clinical setting of acute myocardial infarction and CABG surgery. The results from many of the studies have been disappointing, and no effective cardioprotective therapy is currently used in clinical practice. Several large, multicentre, randomized, controlled clinical trials on cardioprotection have highlighted the challenges of translating ischaemic conditioning and pharmacological cardioprotection strategies into patient benefit. However, a number of cardioprotective therapies have shown promising results in reducing infarct size and improving clinical outcomes in patients with ischaemic heart disease.

AimsRemote ischemic conditioning (RIC) alleviates ischemia–reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection.Methods and resultsWe block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0–T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 μm, p = 0.03 and PWV:0.4 ± 0.21 vs −1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC.ConclusionRIC evokes “vascular conditioning” likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling.Clinical Trial Registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT03984123.

Background The sodium–glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. Methods Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure–volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. Results Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia–reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. Conclusions Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.

Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69 ± 5.8 % ( n  = 11) to 40 ± 6.5 % ( n  = 12), P  = 0.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62 ± 7.6 % controls, n  = 10, versus 61 ± 6.9 % rIPC after cyanamide, n  = 10, P  > 0.05). (ii) In a forearm plethysmography model of endothelial ischaemia–reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia–reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine ( P  = 0.9), but rIPC failed to protect carriers of Glu504Lys polymorphism ( P  = 0.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600 mg od or placebo for 48 h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18 ± 1.03 % and 4.76 ± 0.93 % P  = 0.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87 ± 1.27 % and 3.05 ± 0.53 %, P  = 0.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.

Autophagy is induced in renal tubular cells during acute kidney injury; however, whether this is protective or injurious remains controversial. We address this question by pharmacologic and genetic blockade of autophagy using mouse models of cisplatin- and ischemia–reperfusion-induced acute kidney injury. Chloroquine, a pharmacological inhibitor of autophagy, blocked autophagic flux and enhanced acute kidney injury in both models. Rapamycin, however, activated autophagy and protected against cisplatin-induced acute kidney injury. We also established a renal proximal tubule–specific autophagy-related gene 7–knockout mouse model shown to be defective in both basal and cisplatin-induced autophagy in kidneys. Compared with wild-type littermates, these knockout mice were markedly more sensitive to cisplatin-induced acute kidney injury as indicated by renal functional loss, tissue damage, and apoptosis. Mechanistically, these knockout mice had heightened activation of p53 and c-Jun N terminal kinase, the signaling pathways contributing to cisplatin acute kidney injury. Proximal tubular cells isolated from the knockout mice were more sensitive to cisplatin-induced apoptosis than cells from wild-type mice. In addition, the knockout mice were more sensitive to renal ischemia–reperfusion injury than their wild-type littermates. Thus, our results establish a renoprotective role of tubular cell autophagy in acute kidney injury where it may interfere with cell killing mechanisms.

Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies.