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Objective：To investigate the effect of exercise preconditioning on angiogenesis in ischemic brain tissue in rats with cerebral ischemia-reperfusion injury in the view of VEGF/VEGFR2/dock6 signaling pathway Method：SD male rats were divided into sham group, model group and exercise preconditioning group by random number table method, with 18 rats in each group. The sham operation group and the model group were not given any treatment, while the exercise preconditioning group was given adaptive running training for 3 days at a speed of 10 m/min, once a day for 20 minutes each time. After the adaptive training, the exercise preconditioning group was given formal running training for 3 weeks, continuous training for 6 days a week, rest for 1 day, electric treadmill slope of 0°, speed of 15m/min, 30min/d. Model group and exercise preconditioning group were modified to prepare the middle cerebal artery occlusion (MACO)models by Koizumi thread method, while sham operation group only given skin cutting without thread insertion. Zea longa score and modified neurological severity score (mNSS) were used to score neurological deficit in rats, the relative infarct size of the brain was detected by TTC staining, the morphological changes of the ischemic cerebral cortex was observed by HE staining, the expression of CD31 in ischemic cerebral cortex was detected by immunohistochemistry and the expressions of VEGFA, VEGFR2, Dock6 in ischemic cerebral cortex were detected by western blot. Result：①Zea-Longa scoring：after awaking from anesthetizati, compared with the sham group, the Zea-Longa scores of the other two groups were increased (P<0.01), and there was no statistical significance in the Zea-Longa scores between the two groups. At 72 hours after reperfusion, compared with the sham group, the Zea-Longa score of the rats in the model group was significantly increased (P<0.01)；compared with the model group, the Zea-Longa score of the rats in the exercise preconditioning group was significantly decreased (P<0.05). ②mNSS scoring：At 72 hours after reperfusion, compared with the sham group, the mNSS score of the rats in the model group was significantly increased (P<0.01)；compared with the model group, the mNSS score of the rats in the exercise preconditioning group was significantly decreased (P<0.05).③TTC staining：Compared with the sham group, the cerebral infarction volume in the model group was increased (P<0.01), and compared with the model group, the cerebral infarction volume in the exercise preconditioning group was decreased (P<0.05). ④ HE staining：Compared with the sham group, the model group rats appeared significant pathological changes in the cerebral cortex on the ischemic side. Compared with the model group, the pathological changes of the cerebral cortex on the ischemic side of the rats in the exercise preconditioning group were alleviated. ⑤ Immunohistochemistry of CD31：Compared with the sham group, the expression of CD31 in the ischemic cerebral cortex of the model group was significantly increased (P<0.05). The expression of CD31 in the ischemic cerebral cortex of the exercise preconditioning group was further increased (P<0.05). ⑥Western blot of VEGF, VEGFR2 and Dock6：Compared with the sham group, the expressions of VEGF (P<0.05), VEGFR2 (P<0.05) and Dock6 (P< 0.01)in the ischemic cerebral cortex of the model group were significantly increased；compared with the model group, the expressions of VEGF (P<0.05), VEGFR2 (P<0.05) and Dock6 (P<0.01) in the ischemic cerebral cortex of the exercise preconditioning group were further increased. Conclusion：Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce cerebral ischemia-reperfusion injury, which may be related to the activation of VEGF/VEGFR2/Dock6 signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Ischemia/reperfusion (I/R) may cause irreversible damage to tissues and organs. We evaluated the effects of dexketoprofen on a renal I/R model in rats. Methods: The study included 30 male rats. Control group received 1 mL of saline. Dexketoprofen group received 1 mL (25 mg) of dexketoprofen intraperitoneally. After 60 minutes renal ischemia, 23 hours reperfusion was applied. In Sham group, laparotomy was performed with a medial line incision without any additional procedure. Changes in the plasma malondialdehyde (MDA), renal tissue MDA, plasma glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), BUN, creatinine and albumin levels, and histopathological changes were evaluated. Results: CAT values were significantly lower in Control as compared with the Sham group. Plasma levels of MDA in the Control group were significantly higher than in the Dexketoprofen group. BUN and creatinine values were significantly higher in the Dexketoprofen group. The severity of tissue injury in the Dexketoprofen group was significantly higher than in Control and Sham groups Conclusion: Although dexketoprofen reduces the I/R-induced systemic inflammation, it increases renal tissue damage.

Introduction: Acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) injury is a pro-inflammatory process that activates toll-like receptors (TLRs). Stem cell therapy holds a great promise for kidney repair. Therefore, we investigated the immunomodulatory role of bone marrow stromal cells (BMSCs) on TLR2 and TLR4 expression in AKI in male Sprague-Dawley rats. Methods: BMSCs were isolated from the bone marrow of male rats, cultured in DMEM, and characterized using appropriate markers before transplantation. Renal I/R was induced by 45 minutes bilateral ischemia followed by 24 hours of reperfusion. Rats received intraperitoneal injections of BMSCs (1.5 × 106 cells, i.p, per rat) immediately after termination of renal ischemia. Serum samples were collected pre-and post-stem cells injection for assessment of blood urea nitrogen (BUN) and creatinine (Cr) levels. The kidneys were harvested after 24 hours of reperfusion for structural and molecular analysis. Results: Renal I/R caused severe tissue injuries and increased the level of BUN (166.5 ± 12.9 vs. 18.25 ± 1.75) and Cr (3.7 ± 0.22 vs. 0.87 ± 0.06) compared to the sham group. In addition, mRNA expression of TLR2 and TLR4 elevated in the renal I/R group. Administration of BMSCs improved the functional and structural state of the kidney induced by I/R and down-regulated TLR2 and TLR4 gene expression. Conclusion: The results showed a highly significant renoprotection by BMSCs that indicates their therapeutic potential in I/R injures. These effects are most likely associated with the TLR2/4 signaling pathway via modulation of the inflammatory response cascades.

Introduction: Acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) injury is a pro-inflammatory process that activates toll-like receptors (TLRs). Stem cell therapy holds a great promise for kidney repair. Therefore, we investigated the immunomodulatory role of bone marrow stromal cells (BMSCs) on TLR2 and TLR4 expression in AKI in male Sprague-Dawley rats. Methods: BMSCs were isolated from the bone marrow of male rats, cultured in DMEM, and characterized using appropriate markers before transplantation. Renal I/R was induced by 45 minutes bilateral ischemia followed by 24 hours of reperfusion. Rats received intraperitoneal injections of BMSCs (1.5 × 106 cells, i.p, per rat) immediately after termination of renal ischemia. Serum samples were collected pre-and post-stem cells injection for assessment of blood urea nitrogen (BUN) and creatinine (Cr) levels. The kidneys were harvested after 24 hours of reperfusion for structural and molecular analysis. Results: Renal I/R caused severe tissue injuries and increased the level of BUN (166.5 ± 12.9 vs. 18.25 ± 1.75) and Cr (3.7 ± 0.22 vs. 0.87 ± 0.06) compared to the sham group. In addition, mRNA expression of TLR2 and TLR4 elevated in the renal I/R group. Administration of BMSCs improved the functional and structural state of the kidney induced by I/R and down-regulated TLR2 and TLR4 gene expression. Conclusion: The results showed a highly significant renoprotection by BMSCs that indicates their therapeutic potential in I/R injures. These effects are most likely associated with the TLR2/4 signaling pathway via modulation of the inflammatory response cascades. [ABSTRACT FROM AUTHOR]

Background/Aims: We investigated the regenerative capacity of intravenous administration of bone marrow–derived mononuclear cells (BMMCs) in a rat model of bilateral renal ischemia/reperfusion (IR) injury and the involvement of inflammatory anti-inflammatory and other biological markers in this process. Methods: Rats were subjected to 1h bilateral renal pedicle clamping. BMMCs were injected i.v 1h after reperfusion and tracked by 99mTc and GFP+ BMMCs. Twenty-four hours after reperfusion, renal function and histological changes were evaluated. The mRNA (real time PCR) and protein (ELISA and immuno-staining) expression of biological markers were analyzed. Results: Renal function and structure improved after infusion of BMMCs in the IR group (IR-C). Labeled BMMCs were found in the kidneys after therapy. The expression of inflammatory and biological markers (TLR-2, TRL-4, RAGE, IL-17, HMGB-1, KIM-1) were reduced and the expression of anti-inflammatory and antioxidant markers (IL-10, Nrf2, and HO-1) were increased in IR-C animals compared with IR untreated animals (IR-S). The apoptotic index diminished and the proliferation index increased in IR-C compared with IR-S. Conclusion: The results contribute to our understanding of the role of different biological players in morphofunctional renal improvement and cytoprotection in a post-ischemic reperfusion kidney injury model subjected to cellular therapy.

Epoxyeicosatrienoic acids (EETs) decrease cardiac ischemia-reperfusion injury; however, the mechanism of their protective effect remains elusive. Here, we investigated the cardioprotective action of a novel EET analog, EET-B, in reperfusion and the role of hypoxia-inducible factor (HIF)-1αin such action of EET-B. Adult male rats were subjected to 30 min of left coronary artery occlusion followed by 2 h of reperfusion. Administration of 14,15-EET (2.5 mg/kg) or EET-B (2.5 mg/kg) 5 min before reperfusion reduced infarct size expressed as a percentage of the area at risk from 64.3±1.3% in control to 42.6±1.9% and 46.0±1.6%, respectively, and their coadministration did not provide any stronger effect. The 14,15-EET antagonist 14,15-epoxyeicosa- 5(Z)-enoic acid (2.5 mg/kg) inhibited the infarct size-limiting effect of EET-B (62.5±1.1%). Similarly, the HIF-1α inhibitors 2-methoxyestradiol (2.5 mg/kg) and acriflavine (2 mg/kg) completely abolished the cardioprotective effect of EET-B. In a separate set of experiments, the immunoreactivity of HIF-1α and its degrading enzyme prolyl hydroxylase domain protein 3 (PHD3) were analyzed in the ischemic areas and nonischemic septa. At the end of ischemia, the HIF-1α immunogenic signal markedly increased in the ischemic area compared with the septum (10.31±0.78% vs. 0.34±0.08%). After 20min and 2 h of reperfusion, HIF-1α immunoreactivity decreased to 2.40±0.48% and 1.85±0.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1α immunoreactivity (7.80±0.69% and 6.44±1.37%, respectively) and significantly reduced PHD3 immunogenic signal in ischemic tissue after reperfusion. In conclusion, EET-B provides an infarct size-limiting effect at reperfusion that is mediated by HIF-1α and downregulation of its degrading enzyme PHD3. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Hemorrhagic shock is a common vital condition in obstetrics, and major treatment consists of bleeding control and liquid resuscitation. MicroRNA (miR) has been found to regulate multiple diseases. However, its expression profile in hemorrhagic shock or effects on the ischemia-reperfusion injury in pregnant mice has not been reported yet. PATIENTS AND METHODS: This study generated rat hemorrhagic shock pregnant model, on which real-time quantitative PCR was used to measure miR-34a expressions. MiR-34a inhibitor was applied to specifically suppress miR- 34a expression. Serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured by using the commercial kit. Ischemia- reperfusion injury on rat kidney, lung, liver and intestine tissues was evaluated by using hematoxylin-eosin (HE) staining. RESULTS: In a hemorrhagic shock pregnant rat model, miR-34a expression level was significantly elevated compared to the Normal group (p < 0.05). Application of miR-34a inhibitor effectively suppressed the miR-34a expression in rat kidney, lung, liver and intestine tissues (p < 0.05 compared to normal group). Model rats also had significantly elevated serum MDA and significantly lower SOD levels compared to Normal group (p < 0.05). miR-34a inhibitor reversed this abnorma lity to certain extents (p < 0.05 compared to model group). HE results showed ischemia- reperfusion damage in rat kidney, lung, liver and intestine tissues. miR-34a inhibitor improved such injury. CONCLUSIONS: Suppression of miR-34a could alleviate multi-organ damage after re-perfusion of hemorrhagic shock pregnant rats, probably due to the suppression of oxidative stress. Suppression of miR-34a might work as the treatment target treating multi-organ damage caused by hemorrhagic shock. [ABSTRACT FROM AUTHOR]

The changes of cardiac hemodynamics against the background of ischemia-reperfusion in 40 male and female white rats and their relationship to the level of hydrogen sulfide (H2S) in the blood serum of rats are studied. In the model of ischemiareperfusion we evaluated the parameters of cardiac hemodynamics (microcirculation coefficient, left ventricle oxygen saturation, pressure in right and left ventricle) and content of hydrogen sulfide in the blood serum. It was found that in males background level of microcirculation ratio in the left ventricle and the content of H2S in the blood serum is significantly lower (by 9-18%) than females. Under experimental occlusion of left coronary artery H2S level reduce in blood serum is registered (in males by 64.5%, in females by 51.1%), which is accompanied by inhibition of microcirculation and oxygen supply of cardiomyocytes of the left ventricle (microcirculation rate and oxygen saturation are reduced), by weakening of its contractive capacity and violation of intraventricular hemodynamics (pressure is reduced in left and right ventricle). These changes were more pronounced in males than in females. Reperfusion of coronary vessels in animals of both sexes did not cause total recovery of H2S content in serum and cardiac hemodynamics indicators to background levels, indicating the formation of unrestored coronary circulation syndrome. Іnfusion of NaHS not only prevented ischemia of heart muscle, but also contributed to a more complete recanalization by improving effective perfusion in both males and females. Correlative analysis showed that H2S level in blood serum reveals direct links with microcirculation coefficient, left ventricle oxygen saturation, pressure in right and left ventricle (in males r = 0.54-0.62; in females r = 0.60-0.70). These data suggest an important role of H2S system in the regulation of microcirculation and cardiac hemodynamics in male and female rats on background of ischemia-reperfusion. [ABSTRACT FROM AUTHOR]

During kidney and other organ transplantation, the organ to be transplanted, must inevitably remain out of the body with little or no blood perfusion at all for a long period of time (ischemia). These events have been suggested to cause the formation of oxygen- derived free radicals (OFR). Reperfusion (reintroduction of blood flow) will further exacerbate the initial damage caused by the ischemic insult and may result in the production of free radicals. The aim of this study was to investigate whether induction of brief periods of renal artery occlusion (ischemic pre¬conditioning, IPC) can provide protection from the effects of a subsequent period of ischemia and reperfusion (IR) in the rat kidney."nMaterials and Methods: In this regard, 28 white, male rats were randomly and equally divided into four groups: Control (sham- operated), IPC alone, IR alone (30 min ischemia followed by 10 min reperfusion), and IPC- IR. Preconditioning involved the sequential clamping of the right renal artery for 5 min and declamping for 5 min for a total of 3 cycles. To demonstrate the effectiveness of IPC regimen, vitamin E as an endogenous antioxidant and an index of lipid peroxidation was measured by HPLC after its extraction from right renal venous plasma and right renal tissue."nResults: Results of this study showed that the amount of vitamin E of renal tissue and venous plasma in the IR group had a significant decrease when compared to the control group (P< 0.0001). Whereas the amount of this vitamin in both renal tissue and venous plasma of the IPC- IR group was significantly higher than that in the IR group (P< 0.0001), but did not show any significant difference with the control group."nConclusion: In this study, preconditioning method prevented the reduction of the endogenous antioxidant (Vit. E) in encountering the following sustained ischemic insult. Therefore, we suggest that ischemic preconditioning can be used to protect the Vit. E level of kidney from its subsequent decrease by ischemia and reperfusion."n"n"n"n

Background: Diabetes can increase the risk of coronary heart disease, and also increase the mortality rate of coronary heart disease in diabetic patients. Although reperfusion therapy can preserve the viable myocardium, fatal reperfusion injury can also occur. Studies have shown that diabetes can aggravate myocardial ischemia-reperfusion injury, ERK1/2 can reduce myocardial ischemia-reperfusion injury, but its mechanism in hyperglycemic myocardial ischemia-reperfusion injury is unclear. This study sought to explore the mechanism of extracellular signal-regulated kinase 1/2 (ERK1/2) in hyperglycemic myocardial ischemia reperfusion (I/R) injury., Methods: H9C2 cardiomyocytes were treated with high-glucose (HG) medium plus I/R stimulation to establish a hyperglycemia I/R model in vitro. The cells were treated with LM22B-10 (an ERK activator) or transfected with the constitutive activation of the mitogen-activated protein kinase 1 ( CaMEK ) gene. Myocardial cell apoptosis, mitochondria functional-related indicators, the oxidative stress indexes, and the expression levels of ERK1/2 protein were detected., Results: The HG I/R injury intervention caused an increase in the ratio of apoptotic cardiomyocytes (P<0.05), but the phosphorylation level of the ERK1/2 protein did not increase further. Administering LM22B-10 or transfecting the CaMEK gene significantly activated the phosphorylation levels of ERK1/2 protein and reduced the proportion of cardiomyocyte apoptosis (P<0.05). HG I/R injury increased mitochondrial fission and reduced membrane potential. The intervention reduced the number of punctate mitochondria, increased the average network structure size and median branch length (P<0.01), increased the median network structure size and average branch length (P<0.05), and reduced the colocalization of Drp1 (Dynamin-Related protein1)/TOMM20 (Mitochondrial outer membrane translocation enzyme 20) (P<0.05) and Drp1 with serine 616 phosphorylation (Drp1s616) phosphorylation (P<0.01), thereby reducing mitochondrial fission, increasing membrane potential and mitochondrial function. HG I/R injury increased the level of oxidative stress, while administering LM22B-10 or transfecting the CaMEK gene reduced the level of oxidative stress (P<0.01)., Conclusions: Targeting the activation of ERK1/2 protein phosphorylation reduced mitochondrial fission, increased membrane potential and mitochondrial function, reduced oxidative stress and myocardial cell apoptosis, and alleviated hyperglycemia myocardial I/R injury., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5149/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background and Objective: Hypothyroidism decreases cardiac contractility and heart rate. Since cardiac function is also modulated by diazepam, the aim of this study was to investigate the direct effect of diazepam on the isolated hypothyroid rat heart. Materials and Methods: This experimental study was conducted on 30 rats in four groups (control, hypothyroid, control diazepam and hypotyroid+diazepam). According to Langendorff method, isolated hearts were retrogradly perfused with Krebs solution and passed 3 stages of baseline, ischemia and reperfusion. Cardiac parameters including left ventricular developed pressure, Heart Rate (HR) and Rate Pressure Product (RPP) were calculated. Results: At baseline, heart function significantly decreased in hypothyroid group compared with control and control diazepam groups (P=0.01 & P=0.001 respectively). Percentage decline of HR and RPP at baseline stage after diazepam administration, was significantly different in the control diazepam and hypothyroid+diazepam groups (P=0.001 & P=0.002 respectively). Recovery percentage of RPP in reperfusion stage significantly increased in hypothyroid group (% 60±5) compared with control (% 38±5) and in hypotyroid+diazepam group (% 87±8) compared with hypothyroid group (%60±5), (P<0.0001 & P=0.02, respectively). Conclusion: Administration of diazepam exacerbates the effect of hypothyroidism at baseline and reperfusion stages in rats. In other words, diazepam perfusion leads to greater decline of hypothyroid rat heart function at baseline and higher recovery percentage at the reperfusion stage. These effects can be due to the common effects of hypothyroidism and diazepam on the L-type calcium channels or the amount of oxygen consumption in rats. [ABSTRACT FROM AUTHOR]

Objective: Ischemia/reperfusion (I/R) may cause irreversible damage to tissues and organs. We evaluated the effects of dexketoprofen on a renal I/R model in rats., Methods: The study included 30 male rats. Control group received 1 mL of saline. Dexketoprofen group received 1 mL (25 mg) of dexketoprofen intraperitoneally. After 60 minutes renal ischemia, 23 hours reperfusion was applied. In Sham group, laparotomy was performed with a medial line incision without any additional procedure. Changes in the plasma malondialdehyde (MDA), renal tissue MDA, plasma glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), BUN, creatinine and albumin levels, and histopathological changes were evaluated., Results: CAT values were significantly lower in Control as compared with the Sham group. Plasma levels of MDA in the Control group were significantly higher than in the Dexketoprofen group. BUN and creatinine values were significantly higher in the Dexketoprofen group. The severity of tissue injury in the Dexketoprofen group was significantly higher than in Control and Sham groups CONCLUSION: Although dexketoprofen reduces the I/R-induced systemic inflammation, it increases renal tissue damage., (Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Transactivation of epidermal growth factor receptor (EGFR) may contribute to specific protective responses (e.g. mediated by δ-opioid, bradykinin, or muscarinic receptors). No studies have assessed EGFR involvement in cardioprotection mediated by adenosine receptors (ARs), and the role of EGFR in ischemic preconditioning (IPC) is unclear. We tested EGFR, matrix metalloproteinase (MMP), and heparin-binding EGF (HB-EGF) dependencies of functional protection via A1AR agonism or IPC. Pretreatment of mouse hearts with 100 nM of A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA) or IPC (3 × 1.5-min ischemia/2-min reperfusion) substantially improved recovery from 25-min ischemia, reducing left ventricular diastolic dysfunction up to 50% and nearly doubling pressure development and positive change in pressure over time (+dP/dt). Benefit with both CCPA and IPC was eliminated by inhibitors of EGFR tyrosine kinase (0.3 μM AG1478), MMP (0.3 μM GM6001), or HB-EGF ligand (0.3 ng/ml CRM197), none of which independently altered postischemic outcome. Phosphorylation of myocardial EGFR, Erk1/2, and Akt increased two- to threefold during A1AR agonism, with responses blocked by AG1478, GM6001, and CRM197. Studies in HL-1 myocytes confirm A1AR-dependent Erk1/2 phosphorylation is negated by AG1478 or GM6001, and reduced with CRM197 (as was Akt activation). These data collectively reveal that A1AR- and IPC-mediated functional protection is entirely EGFR and MMP dependent, potentially involving the HB-EGF ligand. Myocardial survival kinase activation (Erk1/2, Akt) by A1AR agonism is similarly MMP/HB-EGF/EGFR dependent. Thus MMP-mediated EGFR activation appears essential to cardiac protection and signaling via A1ARs and preconditioning. [ABSTRACT FROM AUTHOR]

N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endo- vanilloid that selectively activates the transient receptor potential vanilloid type 1 TRPV 1) channel. This study tests the hypothesis that OLDA protects the heart gainstischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT)but not in gene- targeted TRPV1-null mutant (TRPV1~) mice. Hearts of WI or TRPV1' mice were Langendorffly perfused with OLDA (2>< i0~ M) in the presence or absence of GRP8-37 (1 X 10-6 M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 X 10~ M), a selective neurokinin-! receptor antagonist; chelerythrine (5 X 10 6 M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 X i0~ M), a nonselec- tive K~ channel antagonist, followed by 35 mm of global ischemia and 40 mm of reperfusion (1(R). Left ventricular end-diastolic pres- sure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/dt (+dP/dt) were evaluated after L/R. OLDA improved recovery of cardiac function after hR in WI but not TRPV1' hearts by increasing LVDP, CF, and +dP/dt and by decreasing LVEDP. CGRP8-37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WI hearts. Radioimmunoassay showed that the release of substance P (SP) and CORP after OLDA treatment was higher in WI than in TRPV 1~'~ hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during hR injury in WI hearts via CORP and SP release, which is abolished by PKC or K1~ channel antagonists. The protective effect of OLDA is void in TRPV1' hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac hR injury. [ABSTRACT FROM AUTHOR]

Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia-reperfusion (IJR) damage have not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the hypertrophic heart rat (HHR). In this study the sex differences in HHR cardiac function and responses to hR [compared to control normal heart rat (NHR)] were investigated ex vivo. The ventricular weight index was markedly increased in HHR female (7.82 ± 0.49 vs. 4.80 ± 0.10 mg/g; P < 0.05) and male (5.76 ± 0.22 vs. 4.62 ± 0.07 mglg; P < 0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males [maximum first derivative of pressure (dP/dtmax): NHR, 4,036 ± 171 vs. 4,258 ± 152 mmHg/s; and HHR, 3,974 ± 160 vs. 4,540 ± 259 mmHg/s; P < 0.05]. HHR hearts were more susceptible to hR (I = 25 mm, and R = 30 mm) injury than NHR hearts (decreased functional recovery, and increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/dtmax) post-hR relative to male NHR (95.0 ± 12.2% vs. 60.5 ± 9.4%), a resistance to postischemic dysfunction not evident in female HHR (29.0 ± 5.6% vs. 25.9 ± 6.3%). Ventricular fibrillation was suppressed, and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to hR insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection. [ABSTRACT FROM AUTHOR]

Background: The ‘gold standard’ radioactive microsphere (RM) technique for measurement of organ blood flow under various experimental conditions is inaccessible to many researchers due to increasing environmental concerns regarding safety and disposal of low-level radioactive waste materials. A new method using neutron activated microspheres (NAM) has recently been described. Methods: We compared regional myocardial blood flows using the new formulation STERIspheres™ (NAM; 15.0 ± 0.1 [SD] μ m; density 1.5 gr/mL) with RM (15.0 ± 0.1 [SD] μ m; density 1.5 gr/mL) under different experimental conditions during acute ischemia-reperfusion injury in dogs. Random paired combinations of four different RM and NAM were co-injected into the left atrium during autoregulation, coronary occlusion and flow-mediated hyperemia (reperfusion) in the same animal. The left ventricle was divided into non-ischemic and ischemic regions and further subdivided into endocardial, mid-myocardial and epicardial portions. After gamma-counting, blood and myocardial tissue samples ( n = 180) were dried and then shipped to a core facility for neutron activation and analysis. NAM-RM blood flow data were directly compared by ANOVA and regression analysis; Bland and Altman analysis was also performed to assess mean differences in blood flow with NAM-RM. Results: A direct relation for blood flow between NAM-RM was observed; the slope of the relation (1.17 RM ± 0.04 [SEE]) was different from unity but the intercept (0.06 ± 0.06 [SEE]) was not different from the origin. Intermethod mean differences were minimal between NAM-RM in the low to normal range of blood flow and were increased at the higher blood flow levels the latter being of minor physiological consequence. A direct relation for endo/epicardial blood flow ratios between NAM-RM was also observed; the slope of the relation (0.98 RM ± 0.04 [SEE]) and the intercept (0.03 ± 0.06 [SEE]) were not different from unity or the origin, respectively. Conclusions: Results show that in addition to limiting production of radioactive waste materials, NAM accurately measure myocardial blood flow, endocardial/epicardial and ischemic/non-ischemic blood flow distributions over a wide range. We compared myocardial blood flows using paired combinations of neutron activated (NAM) and the ‘gold standard’ radiolabeled microspheres (RM) co-injected during autoregulation, coronary occlusion and flow-mediated hyperemia in an in situ canine ischemia-reperfusion preparation. A direct relation for blood flow and endo/epicardial blood flow ratios between NAM-RM was observed; intermethod mean differences between NAM-RM were minimal in the low to normal blood flow range but increased at higher blood flow levels. These results indicate that NAM accurately measure myocardial blood flow and its transmural distribution in addition to limiting unnecessary production of radioactive laboratory waste products. [ABSTRACT FROM AUTHOR]

ABSTRACT Epidemiological studies show that particulate matter (PM) is the principal instigator of some adverse clinical symptoms involving cardiovascular diseases. PM exposure can increase experimental infarct size and potentiate myocardial ischemia and arrhythmias in experimental MI models such as ischemia-reperfusion (I/R) injury.The present study was aimed to evaluate the effects of particulate matter (PM10) on ischemia- reperfusion induced arrhythmias with emphasis on the protective role of VA as an antioxidant on them. Male Wistar rats were divided into 8 groups (n=10): Control, VAc, Sham, VA, PM1 (0.5 mg/kg), PM2 (2.5 mg/kg), PM3 group (5 mg/kg), PM3 + VA group. Within 48 hours, PM10 was instilled into trachea in two stages. Then the hearts were isolated, transferred to a Langendorff apparatus, and subjected to global ischemia (30 minutes) followed by reperfusion (60 minutes). The ischemia- reperfusion induced ventricular arrhythmias were assessed according to the Lambeth conventions.In the present study,the number, incidence and duration of arrhythmiasduring30 minutes ischemia were demonstrated to be more than those in the reperfusion stage. PM exposure increased significantly the number, incidence and duration of arrhythmias in the ischemia and reperfusion duration. Vanillic acid reduced significantly the number, incidence and duration of arrhythmias during the ischemia and reperfusion period.In summary, the results of this study demonstrated that the protective and dysrhythmic effects of VA in the PM exposure rats in I/R model are probably related to its antioxidant properties.

Background/aims: We investigated the regenerative capacity of intravenous administration of bone marrow-derived mononuclear cells (BMMCs) in a rat model of bilateral renal ischemia/reperfusion (IR) injury and the involvement of inflammatory anti-inflammatory and other biological markers in this process., Methods: Rats were subjected to 1h bilateral renal pedicle clamping. BMMCs were injected i.v 1h after reperfusion and tracked by 99mTc and GFP+ BMMCs. Twenty-four hours after reperfusion, renal function and histological changes were evaluated. The mRNA (real time PCR) and protein (ELISA and immuno-staining) expression of biological markers were analyzed., Results: Renal function and structure improved after infusion of BMMCs in the IR group (IR-C). Labeled BMMCs were found in the kidneys after therapy. The expression of inflammatory and biological markers (TLR-2, TRL-4, RAGE, IL-17, HMGB-1, KIM-1) were reduced and the expression of anti-inflammatory and antioxidant markers (IL-10, Nrf2, and HO-1) were increased in IR-C animals compared with IR untreated animals (IR-S). The apoptotic index diminished and the proliferation index increased in IR-C compared with IR-S., Conclusion: The results contribute to our understanding of the role of different biological players in morphofunctional renal improvement and cytoprotection in a post-ischemic reperfusion kidney injury model subjected to cellular therapy., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

Acute renal failure: From renal physiology to the renal transcriptome. Acute renal failure (ARF) is defined as an abrupt fall in glomerular filtration rate. Fully 5% of all patients admitted to the hospital undergo ARF with an attendant increase in morbidity and mortality. We have studied murine models of ischemia/reperfusion and cisplatin-induced renal failure in detail to determine the physiologic and molecular events that are responsible for the syndrome. Both forms of treatment induce necrosis of the proximal tubules, as well as more subtle changes in distal nephron viability, including apoptosis. Both forms are characterized by reduced renal blood, reduced glomerular filtration rate, and a urine-concentrating defect. Simultaneous with the onset of these morphologic and functional features is the commitment of cells to DNA synthesis and cell division, which is preceded by activation of signal transduction pathways and gene transcription that presumably underlie the morphologic and functional changes responsible for the syndrome. We describe a functional genomic approach using microarray data and available database searches to attempt to predict new targets for investigation of the pathogenesis and treatment of this disease. [ABSTRACT FROM AUTHOR]