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Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1α signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1α and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1α prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1α expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1α signalling.

Background: Abnormal myocardial Nav1.5 expression and function cause lethal ventricular arrhythmias during myocardial ischemia–reperfusion (I/R). Protein inhibitor of activated STAT Y (PIASy)-mediated caveolin-3 (Cav-3) SUMO modification affects Cav-3 binding to the voltage-gated sodium channel 1.5 (Nav1.5). PIASy activity is increased after myocardial I/R, but it is unclear whether this is attributable to plasma membrane Nav1.5 downregulation and ventricular arrhythmias. Methods: Using recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA (shRNA). After two weeks, rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements. Results: PIASy was upregulated by I/R (P < 0.01), with increased SUMO2/3 modification of Cav-3 and reduced membrane Nav1.5 density (P < 0.01). AAV9-PIASy shRNA intraventricular injection into the rat heart downregulated PIASy after I/R, at both mRNA and protein levels (P < 0.05 vs. Scramble-shRNA + I/R group), decreased SUMO-modified Cav-3 levels, enhanced Cav-3 binding to Nav1.5, and prevented I/R-induced decrease of Nav1.5 and Cav-3 co-localization in the intercalated disc and lateral membrane. PIASy silencing in rat hearts reduced I/R-induced fatal arrhythmias, which was reflected by a modest decrease in the duration of ventricular fibrillation (VF; P < 0.05 vs. Scramble-shRNA + I/R group) and a significantly reduced arrhythmia score (P < 0.01 vs. Scramble-shRNA + I/R group). The anti-arrhythmic effects of PIASy silencing were also evidenced by decreased episodes of ventricular tachycardia (VT), sustained VT and VF, especially at the time 5–10 min after ischemia (P < 0.05 vs. Scramble-shRNA + IR group). Using in vitro human embryonic kidney 293 T (HEK293T) cells and isolated adult rat cardiomyocyte models exposed to hypoxia/reoxygenation (H/R), we confirmed that increased PIASy promoted Cav-3 modification by SUMO2/3 and Nav1.5/Cav-3 dissociation after H/R. Mutation of SUMO consensus lysine sites in Cav-3 (K38R or K144R) altered the membrane expression levels of Nav1.5 and Cav-3 before and after H/R in HEK293T cells. Conclusions: I/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Nav1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Nav1.5 downregulation in the plasma membrane of cardiomyocytes, and subsequent ventricular arrhythmias in rats. PIASy was identified as a potential therapeutic target for life-threatening arrhythmias in patients with ischemic heart diseases. [ABSTRACT FROM AUTHOR]

Abstract: We have previously shown that N-n-butyl haloperidol iodide (F2), a newly synthesized compound, reduces ischemia/reperfusion (I/R) injury by preventing intracellular Ca2+ overload through inhibiting L-type calcium channels and outward current of Na+/Ca2+ exchanger. This study was to investigate the effects of F2 on activity and protein expression of the rat myocardial sarcoplasmic reticulum Ca2+–ATPase (SERCA) during I/R to discover other molecular mechanisms by which F2 maintains intracellular Ca2+ homeostasis. In an in vivo rat model of myocardial I/R achieved by occluding coronary artery for 30–60min followed by 0–120min reperfusion, treatment with F2 (0.25, 0.5, 1, 2 and 4mg/kg, respectively) dose-dependently inhibited the I/R-induced decrease in SERCA activity. However, neither different durations of I/R nor different doses of F2 altered the expression levels of myocardial SERCA2a protein. These results indicate that F2 exerts cardioprotective effects against I/R injury by inhibiting I/R-mediated decrease in SERCA activity by a mechanism independent of SERCA2a protein levels modulation. [Copyright &y& Elsevier]

Diabetes patients with painful diabetic neuropathy (PDN) show severe spinal atrophy, suggesting pathological changes of the spinal cord contributes to central sensitization. However, the cellular changes and underlying molecular mechanisms within the diabetic spinal cord are less clear. By using a rat model of type 1 diabetes (T1D), we noted an extensive and irreversible spinal astrocyte degeneration at an early stage of T1D, which is highly associated with the chronification of PDN. Molecularly, acetylation of astrocytic signal transducer and activator of transcription-3 (STAT3) that is essential for maintaining the homeostatic astrocytes population was significantly impaired in the T1D model, resulting in a dramatic loss of spinal astrocytes and consequently promoting pain hypersensitivity. Mechanistically, class IIa histone deacetylase, HDAC5 were aberrantly activated in spinal astrocytes of diabetic rats, which promoted STAT3 deacetylation by direct protein-protein interactions, leading to the PDN phenotypes. Restoration of STAT3 signaling or inhibition of HDAC5 rescued astrocyte deficiency and attenuated PDN in the T1D model. Our work identifies the inhibitory axis of HDAC5-STAT3 induced astrocyte deficiency as a key mechanism underlying the pathogenesis of the diabetic spinal cord that paves the way for potential therapy development for PDN., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Background: Dynamic and precise estimation of blood loss (EBL) is quite important for perioperative management. To date, the Triton System, based on feature extraction technology (FET), has been applied to estimate intra-operative haemoglobin (Hb) loss but is unable to directly assess the amount of blood loss. We aimed to develop a method for the dynamic and precise EBL and estimate Hb loss (EHL) based on artificial intelligence (AI)., Methods: We collected surgical patients' non-recycled blood to generate blood-soaked sponges at a set gradient of volume. After image acquisition and preprocessing, FET and densely connected convolutional networks (DenseNet) were applied for EBL and EHL. The accuracy was evaluated using R2, the mean absolute error (MAE), the mean square error (MSE), and the Bland-Altman analysis., Results: For EBL, the R2, MAE and MSE for the method based on DenseNet were 0.966 (95% CI: 0.962-0.971), 0.186 (95% CI: 0.167-0.207) and 0.096 (95% CI: 0.084-0.109), respectively. For EHL, the R2, MAE and MSE for the method based on DenseNet were 0.941 (95% CI: 0.934-0.948), 0.325 (95% CI: 0.293-0.355) and 0.284 (95% CI: 0.251-0.317), respectively. The accuracies of EBL and EHL based on DenseNet were more satisfactory than that of FET. Bland-Altman analysis revealed a bias of 0.02 ml with narrow limits of agreement (LOA) (-0.47 to 0.52 mL) and of 0.05 g with narrow LOA (-0.87 to 0.97 g) between the methods based on DenseNet and actual blood loss and Hb loss., Conclusions: We developed a simpler and more accurate AI-based method for EBL and EHL, which may be more fit for surgeries primarily using sponges and with a small to medium amount of blood loss., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1806). Dr. YJL, LGZ, HYZ, KHZ, ZYY, KZL, JZ, YWC, BY have a patent 202010324328.5 pending. The other authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Objective: To investigate the change in plasma free 15-F2t-isoprostane fn(15-F(2t)-IsoP) concentration and its relationship with postoperative cardiac function of smoking patients who underwent coronary artery bypass grafting (CABG)., Methods: Sixty patients with coronary artery heart disease were divided into smoking group [n=30, age 54-69 years old, American Heart Association (AHA)II-III] and non-smoking group(n=30, age 58-70 years old, ASA II-III). All the patients were scheduled for CABG under combination anesthesia with isoflurane and fentanyl and conventional cardiopulmonary bypass. Blood samples were drawn from the central vein to measure 15-F(2t)-IsoP at the following time points: before operation (T0); 30 minutes after aortic clamping for cardiopulmonary bypass(T1); 10 and 30 minutes after aortic declamping(T2,T3)., Results: There was no statistical difference in 15-F(2t)-IsoP between two groups at T0, but contents of 15-F(2t)-IsoP in the two groups was increased markedly at T1, compared to those at T0 (P<0.05 and P<0.01 for smoking and non-smoking groups, respectively), and the degree of increase of 15-F(2t)-IsoP in smoking group was significantly higher than that in non-smoking group(P<0.05). During reperfusion period (at T2,T3), the rate of lowering of 15-F(2t)-IsoP in smoking group was slower than that in non-smoking group(P<0.05), and moreover, these patients needed more inotropic support than those in non-smoking group., Conclusion: Smoking patients have weaker anti-oxidation capability during CABG, therefore they have higher incidence of low cardiac function.

Objective: To analyse retrospectively the variation of plasma 15-F2t-isoprostane concentration during cardiac surgery and the relation with early myocardial dysfunction following normothemic cardiac surgery., Methods: Thirty patients scheduled for coronary artery bypass graft surgery using normothermic cardiopulmonary bypass (CPB) and warm intermittent blood, crystalloid cardioplegia were enrolled. Patients were divided into two groups treated with (group II) or without (group I) positive inotropic drugs. Central venous blood was sampled at baseline, 30 minutes after global myocardial ischemia, 10, 30 and 120 minutes after aortic declamping (reperfusion). Plasma free 15-F2t-isoprostane was measured with enzyme immunoassay (EIA) using a highly specific rabbit 15-F2t-isoprostane antibody. Cardiac index (CI) was monitored intraoperatively and up to 6 hours following surgery., Results: Plasma free 15-F2t-isoprostane increased significantly during ischemia, remained elevating at 10 minutes after reperfusion (P<0.05 vs. baseline) and began to decline at 30 minutes after reperfusion in the whole population. 15-F2t-isoprostane underwent exponential decay and returned to baseline at 30 minutes after reperfusion in group I that did not need any postoperative inotropic support. In contrast, 15-F2t-isoprostane further increased upon reperfusion and remained significantly higher than baseline at 30 minutes after reperfusion (P<0.05) in group II that needed two or more inotropes to maintain CI greater than 2.2 L x min(-1) x m(-2). Postoperative CI was significantly inversely correlated with the percentage change in plasma free 15-F2t-isoprostane concentration from 10 to 30 minutes after reperfusion (r=-0.95, P<0.01)., Conclusion: It shows a close relationship between free plasma concentrations of 15-F2t-isoprostane and early postoperative cardiac function following coronary artery bypass graft surgery.

Objective: To study the effect of methylprednisolone (MP) on reperfusion injury in severe uncontrolled hemorrhagic shock and explore the possible mechanism involved., Methods: Twelve dogs were randomly divided into two groups, control group (Group I, n=6) and MP group (Group II, n=6). The animals were bled continuously from a femoral artery catheter to produce uncontrolled hemorrhagic shock models. Resuscitation with lactated Ringer's (LR) solution was initiated when mean arterial pressure (MAP) decreased to 20 mm Hg, and MAP was maintained at 30-40 mm Hg. MP (4 mg/kg) was injected intravenously in Group II when resuscitation began. While in Group I, normal saline (NS) was injected instead. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured before exsanguination (T(1)), when MAP decreased to 20 mm Hg (T(2)), 60 min (T(3)) and 120 min (T(4)) after resuscitation. Heart rate, MAP and cardiac output (CO) levels were recorded concomitantly., Results: Infusion volume and hemorrhage volume shed from the superior mesenteric artery in Group I were higher than those in Group II (P<0.01 and P<0.05). After reperfusion, blood SOD levels decreased progressively and MDA levels increased rapidly in Group I. In Group II, blood SOD levels at T(3) and T(4) decreased as compared with that at T(1) but a stepwise increase was present. At T(4), blood SOD level was significantly higher in Group II than in Group I (Plt;0.01). At T(3) and T(4), MDA levels were markedly lower in Group II than in Group I. During reperfusion, MAP was more steady in Group II than in Group I and survival rate after 120 min (at T(4)) was higher in Group II than in Group I (P<0.05)., Conclusions: MP has a protective effect on severe uncontrolled hemorrhagic shock and subsequent reperfusion injury. The mechanism mainly involves the anti-lipid peroxidation activity of MP.