Peroxisome proliferator-activated receptor β/δ agonism protects the kidney against ischemia/reperfusion injury in diabetic rats

Diabetes is an important risk factor for ischemic acute kidney injury, whose pharmacological treatment remains an unmet medical need. The peroxisome proliferator-activated receptor (PPAR) β/δ is highly expressed in the kidney, although its role has not yet been elucidated. Here, we used an in vivo model of renal ischemia/reperfusion (I/R) in streptozotocin-induced diabetic rats (i) to evaluate whether diabetes increases kidney susceptibility to I/R injury and (ii) to investigate the effects of PPARβ/δ activation. The degree of renal injury (1h ischemia/6h reperfusion) was significantly increased in diabetic rats compared with nondiabetic littermates. PPARβ/δ expression was increased after I/R, with the highest levels in diabetic rats. Administration of the selective PPARβ/δ agonist GW0742 attenuated the renal dysfunction, leukocyte infiltration, and formation of interleukin-6 and tumor necrosis factor-α. These effects were accompanied by an increased expression of the suppressor of cytokine signaling (SOCS)-3, which plays a critical role in the cytokine-activated signaling pathway. The beneficial effects of GW0742 were attenuated by the selective PPARβ/δ antagonist GSK0660. Thus, we report herein that PPARβ/δ activation protects the diabetic kidney against I/R injury by a mechanism that may involve changes in renal expression of SOCS-3 resulting in a reduced local inflammatory response.     

DJ-1 protects against cell death following acute cardiac ischemia–reperfusion injury

Novel therapeutic targets are required to protect the heart against cell death from acute ischemia–reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson''s disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia–reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1^L166P and DJ-1^Cys106A mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.     

MicroRNA-22 targeting CBP protects against myocardial ischemia–reperfusion injury through anti-apoptosis in rats

MicroRNAs are extensively involved in the pathogenesis of major cardiovascular diseases by suppressing target gene expression. Recent studies have reported that microRNA-22 (miR-22) may be implicated in ischemia–reperfusion (I/R) induced myocardial injury. However, the specific function of miR-22 in myocardial I/R injury is far from clear nowadays. The present study was designed to determine the role of miR-22 in myocardial I/R injury and investigate the underlying cardio-protective mechanism. The rat myocardial I/R injury model was induced by occluding the left anterior descending coronary artery for 30 min followed by 12 h reperfusion. As predicted, adenovirus-mediated miR-22 overexpression markedly reduced the release of creatine kinase and lactate dehydrogenase, infarct size and cardiomyocytes apoptosis. Moreover, CREB binding protein (CBP) as a potential miR-22 target by bioinformatics was significantly inhibited after miR-22 transfection. We also found that p53 acetylation activity, pro-apoptotic related genes Bax and p21 levels were all decreased associated with the down-regulation of CBP. In conclusion, our data demonstrate that miR-22 could inhibit apoptosis of cardiomyocytes through one of its targets, CBP. Thus, miR-22 may constitute a new therapeutic target for the prevention of myocardial I/R injury.     

The protective effects and potential mechanism of Calpain inhibitor Calpeptin against focal cerebral ischemia–reperfusion injury in rats

To demonstrate the protective effects of Calpeptin as the Calpain inhibitor against focal cerebral ischemia–reperfusion injury in rats and to explore it’s possible mechanism. 96 rats were randomly divided into four groups. The model of middle cerebral artery occlusion was used for the research of focal cerebral ischemia. Using this animal model, the effects of Calpeptin on the neurological functions, infarction volume and infarction volume percentage of brain, Caspase-3 expression and neuronal apoptosis in hippocampal CA1 sector after focal cerebral ischemia–reperfusion injury in rats were investigated. The current results confirmed that Calpeptin as the Calpain inhibitor might paly an important role for neuroprotection against focal cerebral ischemia–reperfusion injury. Calpeptin could reduce the neuronal apoptosis in hippocampal CA1 sector when the rats was subjected to the focal cerebral ischemia–reperfusion, the potential mechanism might be related to the inhibition of the expression of Caspase-3 by Calpeptin. However, it is still unknown to what the exact mechanism of Calpeptin inhibits the activation of Caspase-3 in this process. Therefore, further research needs to be done to unravel the underlying mechanisms in the future.     

The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats

The advent of infectious molecular clones of Hepatitis C virus (HCV) has unlocked the understanding of HCV life cycle. However, packaging of the genomic RNA, which is crucial to generate infectious viral particles, remains poorly understood. Molecular interactions of the domain 1 (D1) of HCV Core protein and HCV RNA have been described in vitro. Since compaction of genetic information within HCV genome has hampered conventional mutational approach to study packaging in vivo, we developed a novel heterologous system to evaluate the interactions between HCV RNA and Core D1. For this, we took advantage of the recruitment of Vpr fusion-proteins into HIV-1 particles. By fusing HCV Core D1 to Vpr we were able to package and transfer a HCV subgenomic replicon into a HIV-1 based lentiviral vector. We next examined how deletion mutants of basic sub-domains of Core D1 influenced HCV RNA recruitment. The results emphasized the crucial role of the first and third basic regions of D1 in packaging. Interestingly, the system described here allowed us to mobilise full-length JFH1 genome in CD81 defective cells, which are normally refractory to HCV infection. This finding paves the way to an evaluation of the replication capability of HCV in various cell types.     

The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats

Apoptosis is one of the major mechanisms of cell death during cerebral ischemia and reperfusion injury. Flurbiprofen has been shown to reduce cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanism remains unclear. This study aimed to investigate the potential association between the neuroprotective effect of flurbiprofen and the apoptosis inhibiting signaling pathways, in particularly the Akt/GSK-3β pathway. A focal cerebral ischemia rat model was subjected to middle cerebral artery occlusion (MCAO) for 120 min and then treated with flurbiprofen at the onset of reperfusion. The infarct volume and the neurological deficit scores were evaluated at 24 h after reperfusion. Cell apoptosis, apoptosis-related proteins and the levels of p-Akt and p-GSK-3β in ischemic penumbra were measured using TUNEL and western blot. The results showed that administration of flurbiprofen at the doses of 5 and 10 mg/kg significantly attenuated brain ischemia/reperfusion injury, as shown by a reduction in the infarct volume, neurological deficit scores and cell apoptosis. Moreover, flurbiprofen not only inhibited the expression of Bax protein and p-GSK-3β, but also increased the expression of Bcl-2 protein, the ratio of Bcl-2/Bax as well as the P-Akt level. Taken together, these results suggest that flurbiprofen protects the brain from ischemia/reperfusion injury by reducing apoptosis and this neuroprotective effect may be partly due to the activation of Akt/GSK-3β signaling pathway.     

TNF-α inhibitor protects against myocardial ischemia/reperfusion injury via Notch1-mediated suppression of oxidative/nitrative stress

TNF-α inhibitor reportedly protects against myocardial ischemia/reperfusion (MI/R) injury. It can also increase Notch1 expression in inflammatory bowel disease, revealing the regulation of Notch1 signaling by TNF-α inhibitor. However, the interaction between TNF-α inhibitor and Notch1 signaling in MI/R remains unclear. This study aimed to determine the involvement of TNF-α inhibitor with Notch1 in MI/R and delineate the related mechanism. Notch1-specific small interfering RNA (20 μg) or Jagged1 (a Notch ligand, 12 μg) was delivered through intramyocardial injection. Forty-eight hours after injection, mice received 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress) or 24 h (for infarct size and cardiac function) of reperfusion. Ten minutes before reperfusion, mice randomly received an intraperitoneal injection of vehicle, etanercept, diphenyleneiodonium, 1400W, or EUK134. Finally, downregulation of Notch1 significantly reversed the alleviation of MI/R injury induced by etanercept, as evidenced by enlarged myocardial infarct size, suppressed cardiac function, and increased myocardial apoptosis. Moreover, Notch1 blockade increased the expression of inducible NO synthase (iNOS) and gp^91phox, enhanced NO and superoxide production, and accelerated their cytotoxic reaction product, peroxynitrite. Furthermore, NADPH inhibition with diphenyleneiodonium or iNOS suppression with 1400W mitigated the aggravation of MI/R injury induced by Notch1 downregulation in mice treated with etanercept. Additionally, either Notch1 activation with Jagged1 or peroxynitrite decomposition with EUK134 reduced nitrotyrosine content and attenuated MI/R injury. These data indicate that MI/R injury can be attenuated by TNF-α inhibitor, partly via Notch1 signaling-mediated suppression of oxidative/nitrative stress.     

Ebselen ameliorates renal ischemia–reperfusion injury via enhancing autophagy in rats

Renal ischemia–reperfusion (I/R) injury is one of the most common causes of chronic kidney disease (CKD). It brings unfavorable outcomes to the patients and leads to a considerable socioeconomic burden. The study of renal I/R injury is still one of the hot topics in the medical field. Ebselen is an organic selenide that attenuates I/R injury in various organs. However, its effect and related mechanism underlying renal I/R injury remains unclear. In this study, we established a rat model of renal I/R injury to study the preventive effect of ebselen on renal I/R injury and further explore the potential mechanism of its action. We found that ebselen pretreatment reduced renal dysfunction and tissue damage caused by renal I/R. In addition, ebselen enhanced autophagy and inhibited oxidative stress. Additionally, ebselen pretreatment activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effect of ebselen was suppressed by autophagy inhibitor wortmannin. In conclusion, ebselen could ameliorate renal I/R injury, probably by enhancing autophagy, activating the Nrf2 signaling pathway, and reducing oxidative stress.

     

Acute treatment with Danshen-Gegen decoction protects the myocardium against ischemia/reperfusion injury via the redox-sensitive PKC?/mKATP pathway in rats

Danshen-Gegen (DG) decoction, an herbal formulation comprising Radix Salvia Miltiorrhiza and Radix Puerariae Lobatae, is prescribed for the treatment of coronary heart disease in Chinese medicine. Experimental and clinical studies have demonstrated that DG decoction can reduce the extent of atherosclerosis. In the present study, using an ex vivo rat model of myocardial ischemia/reperfusion (I/R) injury, we investigated the myocardial preconditioning effect of an aqueous DG extract prepared from an optimized weight-to-weight ratio of Danshen and Gegen. Short-term treatment with DG extract at a daily dose of 1 g/kg and 2 g/kg for 3 days protected against myocardial I/R injury in rats. The cardioprotection afforded by DG pretreatment was paralleled by enhancements in mitochondrial antioxidant status and membrane structural integrity, as well as a decrease in the sensitivity of mitochondria to Ca²⁺-stimulated permeability transition in vitro, particularly under I/R conditions. Short-term treatment with the DG extract also enhanced the translocation of PKC? from the cytosol to mitochondria in rat myocardium, and this translocation was inhibited by α-tocopherol co-treatment with DG extract in rats. Short-term DG treatment may precondition the myocardium via a redox-sensitive PKC?/mK_ATP pathway, with resultant inhibition of the mitochondrial permeability transition through the opening of mitochondrial K_ATP channels. Our results suggest that clinical studies examining the effectiveness of DG extract given prophylactically in affording protection against myocardial I/R injury would be warranted.     

Role of CC-chemokine receptor 5 on myocardial ischemia–reperfusion injury in rats

The expression level of CC-chemokine receptor 5 (CCR5) is enhanced post inflammatory stimulations and might play a crucial role on inflammatory cells infiltration post myocardial ischemia. The purpose of this study was to evaluate the role of CCR5 on myocardial ischemia–reperfusion (I/R) injury in rats. Adult male rats were randomized to sham group, I/R group (I/R, 30 min coronary artery occlusion followed by 2-h reperfusion), ischemic preconditioning (I/R + Pre), CCR5 antibody group [I/R + CCR5Ab (0.2 mg/kg)], and CCR5 agonist group [I/R + CCR5Ago, RNATES (0.1 mg/kg)], n = 12 each group. The serum level of creatine kinase (CK) and tumor necrosis factor α (TNF-α) were measured by ELISA. Myocardial infarction size and myeloperoxidase (MPO) activity were determined. Myocardial protein expression of CCR5 and intercellular adhesion molecule-1 (ICAM-1) were evaluated by Western blotting and immunohistochemistry staining, respectively. Myocardial nuclear factor-kappa B (NF-κB) activity was assayed by electrophoretic mobility shift assay. Myocardial CCR5 protein expression was significantly reduced in I/R + Pre group (P < 0.05 vs. I/R) and further reduced in I/R + CCR5Ab group (P < 0.05 vs. I/R + Pre). LVSP and ±dP/dt _max were significantly lower while serum CK and TNF-α as well as myocardial MPO activity, ICAM-1 expression, and NF-κB activity were significantly higher in I/R group than in sham group (all P < 0.05), which were significantly reversed by I/R + Pre (all P < 0.05 vs. I/R) and I/R + CCR5Ab (all P < 0.05 vs. I/R + Pre) while aggravated by I/R + CCR5Ago (all P < 0.05 vs. I/R). Our results suggest that blocking CCR5 attenuates while enhancing CCR5 aggravates myocardial I/R injury through modulating inflammatory responses in rat heart.     

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia–reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia–reperfusion injury in clinically relevant in vivo murine models of ischemia–reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia–reperfusion injury and their possible mechanisms of cardioprotection.     

Blockade of PKCβ protects against remote organ injury induced by intestinal ischemia and reperfusion via a p66shc-mediated mitochondrial apoptotic pathway

Intestinal ischemia–reperfusion (I/R) is a serious clinical dilemma with high morbidity and mortality. Remote organ damage, especially acute lung injury and liver injury are common complications that contribute to the high mortality rate. We previously demonstrated that activation of PKCβII is specifically involved in the primary injury of intestinal I/R. Considering the tissue-specific features of PKC activation, we hypothesized that some kind of PKC isoform may play important roles in the progression of secondary injury in the remote organ. Mice were studied in in vivo model of intestinal I/R. The activation of PKC isoforms were screened in the lung and liver. Interestingly, we found that PKCβII was also activated exclusively in the lung and liver after intestinal I/R. PKCβII suppression by a specific inhibitor, LY333531, significantly attenuated I/R-induced histologic damage, inflammatory cell infiltration, oxidative stress, and apoptosis in these organs, and also alleviated systemic inflammation. In addition, LY333531 markedly restrained p66shc activation, mitochondrial translocation, and binding to cytochrome-c. These resulted in the decrease of cytochrome-c release and caspase-3 cleavage, and an increase in glutathione and glutathione peroxidase. These data indicated that activated PKC isoform in the remote organ, specifically PKCβII, is the same as that in the intestine after intestinal I/R. PKCβII suppression protects against remote organ injury, which may be partially attributed to the p66shc-cytochrome-c axis. Combined with our previous study, the development of a specific inhibitor for prophylaxis against intestinal I/R is promising, to prevent multiple organ injury.     

Valsartan preconditioning protects against myocardial ischemia–reperfusion injury through TLR4/NF-κB signaling pathway

Toll-like receptor 4 (TLR4) activation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. The activated TLR4 is capable of activating a variety of proinflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Valsartan as a kind of Angiotensin II type 1 receptor blockers is gradually used for the treatment of ischemic heart disease depending on its anti-inflammation function. Therefore, we hypothesized that valsartan protects against myocardial I/R injury by suppressing TLR4 activation. We constructed the rat model of myocardial I/R injury. The rats were pretreated with valsartan for 2 weeks, and then subjected to 30 min ischemia and 2 h reperfusion. TLR4 and Nuclear factor kappa-B (NF-κB) levels were detected by quantitative real-time PCR and western blot. In order to evaluate myocardial damage, the myocardial infarct size, histopathologic changes, and the release of myocardial enzymes, proinflammation cytokines and Angiotensin II were analyzed by triphenyl tetrazolium chloride (TTC) staining, light microscopy, and enzyme-linked immunosorbent assay (ELISA), respectively. Valsartan preconditioning inhibited TLR4 and NF-κB expressions concomitant with an improvement in myocardial injury, such as smaller infarct size, fewer release of myocardial enzymes, and proinflammation mediators. These findings suggest that valsartan plays a pivotal role in the protective effects on myocardial I/R injury. This protection mechanism is possibly due to its anti-inflammation function via TLR4/NF-κB signaling pathway.     

Melatonin protects against myocardial ischemia–reperfusion injury by elevating Sirtuin3 expression and manganese superoxide dismutase activity

Myocardial ischemia–reperfusion (MI/R) injury is a crucial cause for mortality throughout the world. Recent studies indicated that melatonin might exert profound cardio-protective effect in MI/R injury. However, the underlying mechanisms are not completely understood. In the current study, we aimed to explore the potential effect of melatonin in the pathological process of MI/R. Both in vivo MI/R model and in vitro H9c2 cell line simulated I/R (SIR) model were applied with or without melatonin supplementation. We found that Sirtuin3 (Sirt3) expression and activity were markedly decreased under MI/R and SIR conditions. Melatonin treatment significantly increased myocardial Sirt3 expression, and alleviated MI/R-induced cardiac morphology changes and cardiac dysfunction, as well as myocardial apoptosis level. In addition, DHE and JC-1 staining results demonstrated that melatonin reduced mitochondrial reactive oxygen species (ROS) generation and restored ATP production after SIR injury via elevating Sirt3 expression. By using siRNA targeting Sirt3, we confirmed that the beneficial effects of melatonin were dependent on Sirt3, which in turn deacetylated and activated manganese superoxide dismutase (MnSOD). Collectively, the current study demonstrated the protective effect of melatonin against MI/R injury via alleviating myocardial oxidative stress. Moreover, these beneficial effects were associated with the deacetylation modification of Sirt3 on MnSOD.     

Monoamine oxidase-induced hydroxyl radical production and cardiomyocyte injury during myocardial ischemia–reperfusion in rats

To elucidate the involvement of monoamine oxidase (MAO) in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion, we applied microdialysis technique to the heart of anesthetized rats. Dialysate samples were collected during 30?min of induced ischemia followed by 60?min of reperfusion. We monitored dialysate 3,4-dihydrobenzoic acid (3,4-DHBA) concentration as an index of hydroxyl radical production using a trapping agent (4-hydroxybenzoic acid), and dialysate myoglobin concentration as an index of cardiomyocyte injury in the ischemic region. The effect of local administration of a MAO inhibitor, pargyline, was investigated. Dialysate 3,4-DHBA concentration increased from 1.9?±?0.5?nM at baseline to 3.5?±?0.7?nM at 20–30?min of occlusion. After reperfusion, dialysate 3,4-DHBA concentration further increased reaching a maximum (4.5?±?0.3?nM) at 20–30?min after reperfusion, and stabilized thereafter. Pargyline suppressed the averaged increase in dialysate 3,4-DHBA concentration by ～72% during occlusion and by ～67% during reperfusion. Dialysate myoglobin concentration increased from 235?±?60?ng/ml at baseline to 1309?±?298?ng/ml at 20–30?min after occlusion. After reperfusion, dialysate myoglobin concentration further increased reaching a peak (5833?±?1017?ng/ml) at 10–20?min after reperfusion, and then declined. Pargyline reduced the averaged dialysate myoglobin concentration by ～56% during occlusion and by ～41% during reperfusion. MAO plays a significant role in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion.     

Noscapine protects the H9c2 cardiomyocytes of rats against oxygen–glucose deprivation/reperfusion injury

Molecular Biology Reports - Noscapine is an antitumor alkaloid derived from Papaver somniferum plants. Our previous study has demonstrated that exposure of noscapine on primary murine fetal...     

Sufentanil protects the rat myocardium against ischemia–reperfusion injury via activation of the ERK1/2 pathway

Sufentanil, a lipophilic opioid, is the most frequently used clinical drug for ischemic heart disease. The effects of sufentanil on MAPK signaling in ischemic heart disease were explored. The effects of sufentanil on ischemia–reperfusion (IR)-induced myocardial injury in a rat model were examined. The serum levels of CK, LDH, MDA and SOD, and the activities of Na⁺–K⁺-ATPase and Ca²⁺–Mg²⁺-ATPase were measured. The levels of total and phosphorylated ERK1/2, JNK, and p38 were measured by western blotting in the heart, and the myocardial H9C2 cell line was studied. Using the Cell Counting Kit-8, the growth rate of H9C2 cells affected by sufentanil was studied. The serum levels of CK, LDH and MDA were higher in the IR group than in the SO and SUF groups. The SOD level, as well as the activities of Na⁺–K⁺-ATPase and Ca²⁺–Mg²⁺-ATPase, were lower in the SO and SUF groups than in the IR group. The phosphorylated ERK1/2 level was lower in the IR group than in the SO and SUF groups. The growth rate of H9C2 cells increased with the concentration of sufentanil and the exposure time. The phosphorylated ERK level was upregulated by 4–12 h of sufentanil exposure, indicating that the effects were time-dependent. Furthermore, an inhibition of ERK signaling by chemical inhibition suppressed the sufentanil-mediated increase in the growth rate of H9C2 cells. Sufentanil appears to be beneficial for cases of worsening ischemic heart disease. Further studies are necessary before a clinical application is considered.     

Lipopolysaccharide pretreatment protects against ischemia/reperfusion injury via increase of HSP70 and inhibition of NF-κB

It has been reported that pretreatment of rats with lipopolysaccharide (LPS) increases myocardial functional recovery in ischemia/reperfusion (I/R) hearts. However, the mechanisms by which LPS induces cardioprotection against I/R injury have not been fully elucidated. In this study, we pretreated rats with LPS (1.0 mg/kg) 24 h before they were subjected to I/R injury, and then examined the roles of heat shock protein-70 (HSP70) and nucleus factor-κB (NF-κB) in LPS-induced cardioprotection. We observed that pretreatment with low-dose LPS resulted in significantly increased levels of HSP70 in the myocardium, which could dramatically inhibit NF-κB translocation and reduce degradation of inhibitory κB. Inhibition of NF-κB, in turn, attenuated release of inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, and IL-6) and reduced apoptosis of myocardium and infarct area following I/R injury. Moreover, HSP70 could ameliorate oxidative stress following I/R injury. To further investigate whether increase of HSP70 might be responsible for protection of the myocardium against I/R injury, we co-administered the HSP70 inhibitor, quercetin, with LPS before I/R injury. We found that LPS-induced cardioprotection was attenuated by co-administration with quercetin. Herein, we concluded that increased levels of HSP70 through LPS pretreatment led to inhibition of NF-κB activity in the myocardium after I/R injury. Our results indicated that LPS-induced cardioprotection was mediated partly through inhibition of NF-κB via increase of HSP70, and LPS pretreatment could provide a means of reducing myocardial I/R injury.