Remote Ischemic Pre-Conditioning (RIPC).

Ischemic pre-conditioning has been shown to protect hearts against ischemia/reperfusion (I/R)-induced cardiac injury. However, it is not feasible in clinic. Many researchers have tried to introduce brief I/R in skeletal muscle to mimic cardiac ischemic pre-conditioning, called remote ischemia pre-conditioning (RIPC). Studies from our group and other groups have shown that RIPC induces the release of cytokines from skeletal muscle (myokines) for tissue protection. Myokines play a central role in repair, inflammatory, and immune responses after injury. Thus, the detailed protocol for RIPC might be useful for researchers to study mechanisms underlying RIPC-mediated tissue protection and crosstalk. Here, we describe a detailed RIPC protocol and show MG53 secretion after RIPC into the blood.

Ischemia preconditioning alleviates ischemia/reperfusion injury-induced coronary no-reflow and contraction of microvascular pericytes in rats.

BACKGROUND: Ischemia preconditioning (IPC) ameliorates coronary no-reflow induced by ischemia/reperfusion (I/R) injury, and pericytes play an important role in microvascular function. However, it is unclear whether IPC exerts a protective effect on coronary microcirculation and regulates the pericytes. OBJECTIVE: The purpose of this study was to assess whether IPC improves coronary microvascular perfusion and reduces pericyte constriction after myocardial I/R injury. METHODS: Rats were randomly divided into three groups: the sham group, the I/R group, and the IPC + I/R group. The left anterior descending artery (LAD) of rats in the I/R group were ligated for 45 min, and the rats in the IPC + I/R group received 4 episodes of 6min occlusion followed by 6min reperfusion before the LAD was ligated. After 24 h of reperfusion, the area of no-reflow, and area at risk were evaluated with thioflavin-S and Evens blue staining, and infarct size with triphenyl tetrazolium chloride staining, respectively. Besides, fluorescent microspheres were perfused to enable visualization of the non-obstructed coronary vessels. Cardiac pericytes and microvascular were observed by immunofluorescence, and the diameter of microvascular at the site of the pericyte somata was analyzed. RESULTS: The infarct size, and area of no-reflow in the IPC + I/R group were significantly reduced compared with the I/R group (infarct size, 33.5% ± 11.9% vs. 49.2% ± 9.4%, p = 0.021；no-reflow, 12.7% ± 5.2% vs. 26.6% ± 5.0%, p < 0.001). IPC improved microvascular perfusion and reduced the percentage of the blocked coronary capillary. Moreover, we found that cardiac pericytes were widely distributed around the microvascular in various regions of the heart, and expressed the contractile protein α-smooth muscle actin. The microvascular lumen diameter at pericyte somata was reduced after I/R (4.3 ± 1.0 µm vs. 6.5 ± 1.2 µm, p < 0.001), which was relieved in IPC + I/R group compared with the I/R group (5.2 ± 1.0 µm vs. 4.3 ± 1.0 µm, p < 0.001). Besides, IPC could reduce the proportion of apoptotic pericytes compared to the I/R group (22.1% ± 8.4% vs. 38.5% ± 7.5%, p < 0.001). CONCLUSION: IPC reduced no-reflow and inhibited the contraction of microvascular pericytes induced by cardiac I/R injury, suggesting that IPC might play a protective role by regulating the pericyte function.

Low-Dose Ammonium Preconditioning Enhances Endurance in Submaximal Physical Exercises.

Preconditioning is often used in medicine to protect organs from ischemic damage and in athletes to enhance the performances. We tested whether low-dose ammonium preconditioning (AMP) could have a beneficial effect on physical exercises (PE). We used Cardiopulmonary Exercise Testing (CPET) on a treadmill to investigate the effects of low-dose AMP on the physical exercise capacity of professional track and field athletes and tested twenty-five athletes. Because of the individual differences between athletes, we performed a preliminary treadmill test (Pre-test) and, according to the results, the athletes were randomly allocated into the AMP and control (placebo, PL) group based on the similarity of the total distance covered on a treadmill. In the AMP group, the covered distance increased (11.3 ± 3.6%, p < 0.02) compared to Pre-test. Similarly, AMP significantly increased O2 uptake volume-VO2 (4.6 ± 2.3%, p < 0.03) and pulmonary CO2 output-VCO2 (8.7 ± 2.8%, p < 0.01). Further, the basic blood parameters (pH, pO2, and lactate) shift was lower despite the greater physical exercise progress in the AMP group compared to Pre-test, whereas in the placebo group there were no differences between Pre-test and Load-test. Importantly, the AMP significantly increased red blood cell count (6.8 ± 2.0%, p < 0.01) and hemoglobin concentration (5.3 ± 1.9%, p < 0.01), which might explain the beneficial effects in physical exercise progress. For the first time, we showed that low-dose AMP had clear beneficial effects on submaximal PE.

[A Potential Role of Adenosine A 2 b Receptor in Mediating Acupuncture Pretreatment Induced Cardioprotection via Influencing Intracellular Calcium Regulator].

It has been shown that ischemia preconditioning (IPC) can attenuate the myocardial injury induced by ischemic and reperfusion. But it was rarely used in clinic due to its inoperability. Previous studies indicate that electroacupuncture (EA) pretreatment can mimic myocardial ischemia preconditioning (MIPC) to produce cardioprotective effect. The activated adenosine A 2 b receptor has been proven to be involved in mediating the cardioprotection of IPC. In the studies on acupuncture analgesia, it was reported that adenosine receptor was activated by acupuncture stimulation, and acupuncture pretreatment can affect the acti-vities of intracellular A 2 b receptor. Based on those mentioned above, it is highly likely that the A 2 b receptor may also participate in the cardioprotection produced by acupuncture pretreatment. In this paper, we comprehensively reviewed relevant studies regarding 1) the cardioprotective effect of IPC and its limitations, 2) the similar cardioprotection produced by both acupuncture pre-treatment and IPC, 3) the mechanism underlying myocardial ischemic injury and intracellular calcium regulation, 4) the acti-vation of adenosine receptors and effects of acupuncture, 5) the relationship between adenosine receptors and intracellular calcium ion, and 6) the effect of acupuncture on adenosine receptors, so as to provide a novel assumption that A 2 b receptor may be a key factor in mediating the cardioprotection of acupuncture pretreatment. Our future research will systematically explore the me-chanism of acupuncture pretreatment in protecting ischemic myocardium from myocardial cell adenosine A 2 b receptor and intracellular calcium signal transduction related factors.

Effect of Autophagy Inhibition on the Protection of Ischemia Preconditioning against Myocardial Ischemia/Reperfusion Injury in Diabetic Rats.

BACKGROUND: Ischemia preconditioning (IPC) remains the most powerful intervention of protection against myocardial ischemia/reperfusion injury (IRI), but diabetes can weaken or eliminate its cardioprotective effect and detailed mechanisms remain unclear. In this study, we aimed to explore whether changes of autophagy in the diabetic condition are attributable to the decreased cardioprotective effect of IPC. METHODS: Sixty diabetic male Sprague-Dawley rats were randomly divided into the control (C), IRI, rapamycin (R), wortmannin (W), rapamycin + IPC (R + IPC), and wortmannin + IPC (W + IPC) groups. The in vivo rat model of myocardial IRI was established by ligaturing and opening the left anterior descending coronary artery via the left thoracotomy. Durations of ischemia and reperfusion are 30 min and 120 min, respectively. Blood samples were taken at 120 min of reperfusion for measuring serum concentrations of troponin I (TnI) and creatine kinase isoenzyme MB (CK-MB) using the enzyme-linked immunosorbent assay. The infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining. The expressions of LC3-II, beclin-1, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and P-Akt/Akt ratio in the ischemic myocardium were assessed by Western blotting. RESULTS: Compared to the IRI group, infarct size (56.1% ± 6.1% vs. 75.4 ± 7.1%, P < 0.05), serum cTnI (0.61 ± 0.21 vs. 0.95 ± 0.26 ng/ml, P < 0.05), and CK-MB levels (6.70 ± 1.25 vs. 11.51 ± 2.35 ng/ml, P < 0.05) obviously decreased in the W + IPC group. Compared with the C group, myocardial expressions of LC3-II (0.46 ± 0.04 and 0.56 ± 0.04 vs. 0.36 ± 0.04, P < 0.05) and beclin-1 (0.34 ± 0.08 and 0.38 ± 0.07 vs. 0.24 ± 0.03, P < 0.05) evidently increased, and myocardial expressions of mTOR (0.26 ± 0.08 and 0.25 ± 0.07 vs. 0.38 ± 0.06, P < 0.05), PI3K (0.29 ± 0.04 and 0.30 ± 0.03 vs. 0.38 ± 0.02, P < 0.05), and P-Akt/Akt ratio (0.49 ± 0.10 and 0.48 ± 0.06 vs. 0.72 ± 0.07, P < 0.05) markedly decreased in the IRI and R groups, indicating an increased autophagy. Compared with the IRI group, myocardial expression of beclin-1 (0.26 ± 0.03 vs. 0.34 ± 0.08, P < 0.05) significantly decreased, and myocardial expressions of mTOR (0.36 ± 0.04 vs. 0.26 ± 0.08, P < 0.05), PI3K (0.37 ± 0.03 vs. 0.29 ± 0.04, P < 0.05), and P-Akt/Akt ratio (0.68 ± 0.05 vs. 0.49 ± 0.10, P < 0.05) increased obviously in the W + IPC group, indicating a decreased autophagy. CONCLUSIONS: Increased autophagy in the diabetic myocardium is attributable to decreased cardioprotection of IPC, and autophagy inhibited by activating the PI3K-Akt-mTOR signaling pathway can result in an improved protection of IPC against diabetic myocardial IRI.

1H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning.

Background OBJECTIVE: The cerebral ischemia/reperfusion greatly influences brain metabolism. Remote ischemia preconditioning (RIPC) is reported to confer neuroprotective effects against cerebral ischemia in animal models and human. This study aims to investigate the metabolomic profiles of cerebrospinal fluid (CSF) in patients treated with repetitive lower limb RIPC and provides an insight into possible mechanism underlying RIPC-induced neuroprotection. METHOD: Fifty healthy patients undergoing minor surgery under spinal anesthesia were randomly allocated to 2 groups: control group (Group C, n = 25) and RIPC treatment group (Group T,n = 25). Repetitive limb RIPC were performed 3 sessions, consisting of three 5-min cycles per session from the day before surgery to the morning on the surgery day. The CSF samples were collected from 48 patients before intrathecal injection of local anesthetic. A proton nuclear magnetic resonance (1H NMR)-based metabonomics approach was used to obtain the CSF metabolic profiles of the samples (n = 24 each). The acquired data were processed with MestReNova and followed by statistical analysis with SIMCA-P. RESULTS: The model obtained with the orthogonal partial least-squares discriminant analysis (OPLS-DA) identified difference of metabolite profiles between two groups. The validation of the discriminant analysis showed that the accuracy of the OPLS-DA model was 81.3%. Sixteen metabolites including glucose, amino-acids and organic acids et al. were identified as the most influential CSF biomarkers for the discrimination between two groups, which are involved in pathways of energy metabolism and amino-acids metabolism. CONCLUSION: 1H NMR spectra combined with pattern recognition analysis offers a new and promising platform to investigate metabolic signatures in patients treated with RIPC. Our results suggest repetitive RIPC mainly changes energy metabolism and amino-acid metabolism in brain, which provides a potential mechanistic understanding of RIPC-induced tolerance to cerebral ischemia.

Cardioprotection of ischemic preconditioning in rats involves upregulating adiponectin.

It has been reported that ischemic preconditioning (IPC) and adiponectin (APN) are cardioprotective in many cardiovascular disorders. However, whether APN mediates the effect of IPC on myocardial injury has not been elucidated. This study was conducted to investigate whether IPC affects myocardial ischemic injury by increasing APN expression. Male adult rats with cardiac knockdowns of APN and its receptors via intramyocardial small-interfering RNA injection were subjected to IPC and then myocardial infarction (MI) at 24 h after IPC. Globular APN (gAd) was injected at 10 min before MI. APN mRNA and protein levels in myocardium as well as the plasma APN concentration were markedly high at 6 and 12 h after IPC. IPC ameliorated myocardial injury as evidenced by improved cardiac functions and a reduced infarct size. Compared with the control MI group, rats in the IPC + MI group had elevated levels of left ventricular ejection fraction and fractional shortening and a smaller MI size (P < 0.05). However, the aforementioned protective effects were ameliorated in the absence of APN and APN receptors, followed by the inhibition of AMP-activated protein kinase (AMPK) phosphorylation, but reversed by gAd treatment in wild-type rats, and AMPK phosphorylation increased (P < 0.05). Overall, our results suggest that the cardioprotective effects of IPC are partially due to upregulation of APN and provide a further insight into IPC-mediated signaling effects.

Sirtinol abrogates late phase of cardiac ischemia preconditioning in rats.

The aim of this study was to investigate the effect of sirtinol, as an inhibitor of sirtuin NAD-dependent histone deacetylases, on myocardial ischemia reperfusion injury following early and late ischemia preconditioning (IPC). Rats underwent sustained ischemia and reperfusion (IR) alone or proceeded by early or late IPC. Sirtinol (S) was administered before IPC. Arrhythmias were evaluated based on the Lambeth model. Infarct size (IS) was measured using triphenyltetrazolium chloride staining. The transcription level of antioxidant-coding genes was assessed by real-time PCR. In early and late IPC groups, IS and the number of arrhythmia were significantly decreased (P < 0.05 and P < 0.01 vs IR, respectively). In S + early IPC, incidences of arrhythmia and IS were not different compared with the early IPC group. However, in S + late IPC the IS was different from the late IPC group (P < 0.05). In late IPC but not early IPC, transcription levels of catalase (P < 0.01) and Mn-SOD (P < 0.05) increased, although this upregulation was not significant in the S + late IPC group. Our results are consistent with the notion that different mechanisms are responsible for early and late IPC. In addition, sirtuin NAD-dependent histone deacetylases may be implicated in late IPC-induced cardioprotection.

Effect of total flavonoid in rabdosia rubescens on tolerant mice models under cerebral anoxia.

OBJECTIVE: To study the protective effect of total flavonoid in rabdosia rubescens on BIT model by brain ischemic tolerance (hereinafter BIT) model of mice. METHOD: BIT model is used to block bilateral common carotid arteries and to copy BIT model of mice. After 10 min of transient ischemia for rats in preconditioning group, the mice in the nimodipine group and naoluotong capsule group were given the total flavonoid in rabdosia rubescens (300 mg/kg, 150 mg/kg, 75 mg/kg) for gavage, sham operation group, ischemia/reperfusion injury (hereinafter IRI) group and BIT group were fed with the same volume of 0.5% sodium carboxymethyl cellulose (CMC) once a day for 5 days. After administration for 1 h on day 5 (120 h), the rats in the other groups except for the sham operation group were treated with blood flow block for 30 min and reperfusion for 22 h. The serum NSE level were measured and the brain NO content and NOS activity changes was measured to observe the histopathological changes of brain tissue. RESULTS: BIT models of mice and in rats were both successfully replicated. The total flavonoid in rabdosia rubescens can decrease the mortality of mice, decrease serum NSE level, increase the content of NO and the activity of NOS in the brain tissue of mice, and improve the pathological damage of cortex and hippocampus of mice. CONCLUSION: The total flavonoid in rabdosia rubescens can stimulate an endogenous protective mechanism by inducing the release of low levels of cytokines NO and NOS, which reduces the release of serum NSE, relieves the brain tissue ischemia-reperfusion injury, and further improves the protection effect of ischemic preconditioning on brain injury. The damage of brain tissue ischemia and reperfusion, and further improve the ischemia Protective effect of preconditioning on brain injury.

Role of cardiac renin angiotensin system in ischemia reperfusion injury and preconditioning of heart.

Cardio-vascular diseases are the leading cause of morbidity and mortality. Ischemia is a state of oxygen deprivation in tissues, whereas reperfusion is restoration of blood flow in ischemic tissues. Myocardial damage of tissue during reperfusion after ischemic insult is known as myocardial ischemia-reperfusion (I/R) injury. It induces damage to cardiac muscle via increasing expression of oxygen, sodium and calcium ions which are responsible in the activation of proteases and cell death. Heart renin angiotensin system (RAS) plays an important role in the myocardial ischemia and reperfusion injury. Angiotensin (1-7) is responsible for vasodilation and angiotensin II for vasoconstriction. Here-in we reviewed how myocardial I/R injury sets in by up-regulation of angiotensin II that leads to increased infarct size, which can be reduced by the use of ACE inhibitors, ACE2 activators and angiotensin II antagonist.

Remote ischemia preconditioning increases red blood cell deformability through red blood cell-nitric oxide synthase activation.

Remote ischemia preconditioning (rIPC), short cycles of ischemia (I) and reperfusion (R) of a region remote from the heart, protects against myocardial I/R injury. This effect is triggered by endothelial derived nitric oxide (NO) production. Red blood cells (RBC) are also capable of NO production and it is hypothesized that the beneficial effect of rIPC in terms of cardioprotection is strengthened by increased RBC dependent NO production and improved RBC function after rIPC maneuver. For this purpose, twenty male participants were subjected to four cycles of no-flow ischemia with subsequent reactive hyperemia within the forearm. Blood sampling and measurement of blood pressures and heart rate were carried out pre intervention, after each cycle and 15 min post intervention at both the non-treated and treated arm. These are the first results that show improved RBC deformability in the treated arm after rIPC cycles 1- 4 caused by significantly increased RBC-NO synthase activation. This in turn was associated to increased NO production in both arms after rIPC cycles 3 + 4. Also, systolic and diastolic blood pressures were decreased after rIPC. The findings lead to the conclusion that the cardioprotective effects associated with rIPC include improvement of the RBC-NOS/NO signaling in RBC.

Characterization of the Langendorff Perfused Isolated Mouse Heart Model of Global Ischemia-Reperfusion Injury: Impact of Ischemia and Reperfusion Length on Infarct Size and LDH Release.

INTRODUCTION: The Langendorff perfused isolated mouse heart model is commonly used to assess the efficacy of cardioprotective therapies, although the duration of ischemia and reperfusion vary considerably between different laboratories. We aimed to provide a thorough characterization of the model with different durations of ischemia and reperfusion by means of 2 different end points-infarct size (IS) using triphenyltetrazolium staining and lactate dehydrogenase (LDH) release. METHODS: C57/BL6 mice hearts were retrograde perfused on a Langendorff apparatus and allocated into 9 groups in a 3 × 3 factorial design-3 ischemic durations (25, 35, and 45 minutes) matched by 3 reperfusion durations (60, 120, and 180 minutes). A protocol of ischemic preconditioning (IPC) was applied to investigate IS and LDH kinetics with different ischemic durations. RESULTS: Infarct size progressively increased with the duration of both ischemia and reperfusion and was found to be independently associated with both determinants. In terms of LDH release kinetics, a peak was observed within the first 10 to 15 minutes of reperfusion and steadily declined thereafter, although a second smaller peak was observed in the 25-minute ischemia group. Only LDH peak release was associated with the ischemia length, with area under the curve (AUC) failing to follow ischemic duration. Interestingly, while IPC reduced IS in all ischemic durations investigated, a significant attenuation of LDH AUC was only observed in the 25-minute index ischemia group. Only a moderately positive correlation was observed between IS and LDH peak (R = .547, P = .006) and AUC (R = .664, P < .001). CONCLUSION: Myocardial IS measured by triphenyltetrazolium staining depends on both the duration of ischemia and the length of the reperfusion period. The LDH assessment may not be the most reliable tool to assess IS and/or to examine cardioprotective effectiveness at various times of ischemia.

Elevation of miR-21, through targeting MKK3, may be involved in ischemia pretreatment protection from ischemia-reperfusion induced kidney injury.

BACKGROUND: Ischemia-reperfusion (IR) causes acute kidney injury (AKI), and ischemia pretreatment may exert protection. Mitogen-activated protein kinase kinase 3 (MKK3), which is involved in the signal transduction pathway in IR-induced injury, is a potential target of miR-21. We aimed to verify the targeting regulation of miR-21 on MKK3 and to explore the effects of miR-21-mediated MKK3 expression changes in AKI. METHODS: Vectors containing the MKK3 3'UTR and mutated MKK3-3U-M were constructed and co-transfected with nonsense miR, miR-21-5p mimics or inhibitor in HEK293 cells. Gene expressions were detected by dual luciferase reporter assay. The effects of miR-21 on mRNA and protein of MKK3 were investigated in HK-2 cells. Male C57BL/6J mice were treated with ischemic preconditioning (IPC) and IR. Kidney functions were assessed through monitoring serum creatinine (Scr) and blood urea nitrogen (BUN). Pathological changes were observed and scored with histological samples of kidney. Expression levels of miR-21, MKK3, interleukin (IL)-6, tumor necrosis factor (TNF)-α before and after IPC and IR were examined by real-time polymerase chain reaction and/or immunohistochemistry. RESULTS: miR-21 regulated the expression of MKK3 via 3'UTR. Following IR, MKK3, IL-6 and TNF-α levels were increased. Scr, BUN and pathological injuries were aggravated, and miR-21 expression was increased. IPC increased miR-21 levels ahead of IR and inhibited the increases in MKK3, IL-6 and TNF-α levels and the aggravation of Scr, BUN and pathological injuries. CONCLUSIONS: miR-21 targets MKK3 in vivo and in vitro, inhibiting the downstream factors IL-6 and TNF-α. Therefore, miR-21 might be involved in protection of IPC against IR of the kidney.

The evolving concept of physiological ischemia training vs. ischemia preconditioning.

Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning.

Cardioprotective effect of remote preconditioning of trauma and remote ischemia preconditioning in a rat model of myocardial ischemia/reperfusion injury.

Remote ischemia preconditioning (RIPC) and remote preconditioning of trauma (RPCT) are two methods used to induce a cardioprotective function against ischemia/reperfusion injury (IRI). However, the underlying mechanisms of these two methods differ. The aim of the present study was to investigate the cardioprotective function of the two methods, and also observe whether combining RIPC with RPCT enhanced the protective effect. In total, 70 male Sprague Dawley rats were randomly divided into five groups, which included the sham, control, RIPC + RPCT, RPCT and RIPC groups. With the exception of the sham group, all the rats were subjected to myocardial IRI through the application of 30 min occlusion of the left coronary artery and 180 min reperfusion. Serum cardiac troponin I (cTnI) levels, myocardial infarct size (IS) and the cardiomyocyte apoptotic index (AI) were assessed. The levels of serum cTnI were lower in the experimental groups when compared with the control group (control, 58.59±12.50 pg/ml; RIPC + RPCT, 46.05±8.62 pg/ml; RPCT, 45.98±11.24 pg/ml; RIPC, 43.46±5.05 pg/ml; P<0.05, vs. control), and similar results were observed for the myocardial IS (control, 48.34±6.79%; RIPC + RPCT, 29.64±4.51%; RPCT, 29.05±8.51%; RIPC, 27.72±6.27%; P<0.05, vs. control) and the AI (control, 31.75±10.65%; RIPC + RPCT, 18.32±9.30%; RPCT, 18.51±9.26%; RIPC, 20.41±3.86%; P<0.05, vs. control). However, no statistically significant differences were observed among the three experimental groups (P>0.05). Therefore, RIPC and RPCT exhibit cardioprotective effects when used alone or in combination. However, a combination of RIPC and RPCT does not enhance the cardioprotective effect observed with the application of either single method. Therefore, for patients undergoing major abdominal surgery, RIPC was considered to be unnecessary, while for patients undergoing other types of non-cardiac major surgery and minimally invasive interventional surgery, RIPC may be useful. In addition, patients with embolism diseases are also liable to IRI when reperfusion treatment such as thrombolysis is conducted. Thus RIPC may also be beneficial for these patients.

Ischemia preconditioning protects astrocytes from ischemic injury through 14-3-3γ.

Stroke is a leading cause of death and disability, and new strategies are required to reduce neuronal injury and improve prognosis. Ischemia preconditioning (IPC) is an intrinsic phenomenon that protects cells from subsequent ischemic injury and might provide promising mechanisms for clinical treatment. In this study, primary astrocytes exhibited significantly less cell death than control when exposed to different durations of IPC (15, 30, 60, or 120 min). A 15-min duration was the most effective IPC to protect astrocytes from 8-hr-ischemia injury. The protective mechanisms of IPC involve the upregulation of protective proteins, including 14-3-3γ, and attenuation of malondialdehyde (MDA) content and ATP depletion. 14-3-3γ is an antiapoptotic intracellular protein that was significantly upregulated for up to 84 hr after IPC. In addition, IPC promoted activation of the c-Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK)-1/2, p38, and protein kinase B (Akt) signaling pathways. When JNK was specifically inhibited with SP600125, the upregulation of 14-3-3γ induced by IPC was almost completely abolished; however, there was no effect on ATP or MDA levels. This suggests that, even though both energy preservation and 14-3-3γ up-regulation were turned on by IPC, they were controlled by different pathways. The ERK1/2, p38, and Akt signaling pathways were not involved in the 14-3-3γ upregulation and energy preservation. These results indicate that IPC could protect astrocytes from ischemia injury by inducing 14-3-3γ and by alleviating energy depletion through different pathways, suggesting multiple protection of IPC and providing new insights into potential stroke therapies.

Early stage effect of ischemic preconditioning for patients undergoing on-pump coronary artery bypass grafts surgery: systematic review and meta-analysis.

BACKGROUND: During the on-pump coronary artery bypass grafts surgery, ischemia/reperfusion injury would happen. Ischemia preconditioning could increase the tolerance against subsequent ischemia and reduce the ischemia/reperfusion injury. However the clinical outcomes of the available trials were different. Methods : We searched the Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2013), the Medline/PubMed and CNKI in March 2013. RevMan 5.1.6 and GRADEprofiler 3.6 were used for statistical analysis and evidence quality assessment. Heterogeneity was evaluated with significance set at P≤0.10. RESULTS: Eighteen randomized controlled trials were included. There were no differences on in-hospital mortality, postoperative myocardial infarction morbidity between ischemia preconditioning and control groups. The heterogeneity of creatine kinase-MB level 24 hours after surgery was obvious. The differences of 72 hours area under the curve of cardiac troponin T (mean differences of -14.50, 95% confidence interval of -21.71 to -7.28) and troponin I (mean differences -181.79, 95% confidence interval of -270.07 to -93.52) after surgery were observed. Conclusion s : All the 18 trails, the positive and the negative results were equal. The meta-analysis results should be interpreted with caution due to limited effective data. Because of high cost-effectiveness, ischemia preconditioning could not be denied completely. Large-scale randomized studies are needed, with the operation procedures and included criteria being more specific.

Increased phosphorylation of mTOR is involved in remote ischemic preconditioning of hippocampus in mice.

Different signaling pathways are involved in tissue protection against ischemia reperfusion (IR) injury, among them mammalian target of rapamycin (mTOR) and related pathways have been examined in many recent studies. Present study evaluated the role of mTOR in remote ischemic preconditioning (RIPC) of hippocampus. Renal ischemia was induced (3 cycles of 5min occlusion and 5min reperfusion of unilateral renal artery) 24h before global brain ischemia (20min bilateral common carotid artery occlusion). Saline or rapamycin (mTOR inhibitor; 5mg/kg, i.p.) was injected 30min before RIPC. mTOR and phosphorylated mTOR (p-mTOR) expression, superoxide dismutase (SOD) activity and retention trial of passive avoidance test were determined 24h after global ischemia. Apoptosis and neuronal cell density were assessed 72h after hippocampal ischemia. RIPC decreased apoptosis (p<0.05 vs. IR), improved memory (p<0.05 vs. IR), and augmented p-mTOR expression and SOD activity after hippocampal ischemia (p<0.05 vs. IR). Rapamycin abolished all protective effects of RIPC (p<0.05 vs. RIPC+IR) suggesting a role for mTOR in RIPC induced hippocampal protection.

A comparative study of cardioprotective effect of three anesthetic agents by measuring serum level of troponin-T after coronary artery bypass grafting.

BACKGROUND: Cardiac surgery is associated with some degree of myocardial injury. Preconditioning first described in 1986 was pharmacologic and non- pharmacologic. Among the long list of anesthetic drugs, isoflurane as an inhaling agent along with midazolam and propofol as injectable substances have been documented to confer some preconditioning effects on myocardium. OBJECTIVES: In this study cardiac Troponin T (cTnT) ,as a reliable marker, was used for evaluating myocardial injury. METHODS: This prospective double blind study was comprised of 60 patients scheduled for CABG and were randomly assigned into three groups who received infusion of propofol or midazolam or isoflorane. Surgical procedures and anesthetics were similar for 3 groups. cTnT measured preoperatively and at 12, 24 and 36hr after arrival in ICU. RESULTS: There were no statistically significant differences in mean cTnT levels between three groups in the preoperative period and 12-24 hours after arrival in ICU. However, mean cTnT in 3 groups at 36 hours after arrival in ICU were different (P< 0.013) and cTnT level was significantly higher in midazolam group (P<0.001) and lowest in isoflurane group (P=0.002). CONCLUSION: There were significant differences on cTnT levels between anesthetic groups of isofluran, midazolam and propofol at 36 hr after surgery. Preconditioning effect of isoflurane was higher than the other two groups.