Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo

2006 ◽  
Vol 291 (3) ◽  
pp. H1138-H1146 ◽  
Author(s):  
Toyotaka Yada ◽  
Hiroaki Shimokawa ◽  
Osamu Hiramatsu ◽  
Yoshisuke Haruna ◽  
Yoshitaka Morita ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
No Production ◽  
Coronary Vasodilatation ◽  
Before And After ◽  
Nos Inhibitor

We have recently demonstrated that endogenous H2O2 plays an important role in coronary autoregulation in vivo. However, the role of H2O2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H2O2 also plays a protective role in coronary I/R injury in dogs in vivo. Canine subepicardial small coronary arteries (≥100 μm) and arterioles (<100 μm) were continuously observed by an intravital microscope during coronary I/R (90/60 min) under cyclooxygenase blockade ( n = 50). Coronary vascular responses to endothelium-dependent vasodilators (ACh) were examined before and after I/R under the following seven conditions: control, nitric oxide (NO) synthase (NOS) inhibitor NG-monomethyl-l-arginine (l-NMMA), catalase (a decomposer of H2O2), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), l-NMMA + catalase, l-NMMA + tetraethylammonium (TEA, an inhibitor of large-conductance Ca2+-sensitive potassium channels), and l-NMMA + catalase + 8-SPT. Coronary I/R significantly impaired the coronary vasodilatation to ACh in both sized arteries (both P < 0.01); l-NMMA reduced the small arterial vasodilatation (both P < 0.01), whereas it increased ( P < 0.05) the ACh-induced coronary arteriolar vasodilatation associated with fluorescent H2O2 production after I/R. Catalase increased the small arterial vasodilatation ( P < 0.01) associated with fluorescent NO production and increased endothelial NOS expression, whereas it decreased the arteriolar response after I/R ( P < 0.01). l-NMMA + catalase, l-NMMA + TEA, or l-NMMA + catalase + 8-SPT further decreased the coronary vasodilatation in both sized arteries (both, P < 0.01). l-NMMA + catalase, l-NMMA + TEA, and l-NMMA + catalase + 8-SPT significantly increased myocardial infarct area compared with the other four groups (control, l-NMMA, catalase, and 8-SPT; all, P < 0.01). These results indicate that endogenous H2O2, in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.

scholarly journals cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING

2018 ◽  
Vol 314 (6) ◽  
pp. G655-G667 ◽  
Author(s):  
Zhao Lei ◽  
Meihong Deng ◽  
Zhongjie Yi ◽  
Qian Sun ◽  
Richard A. Shapiro ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Protective Role ◽  
Guanosine Monophosphate ◽  
Independent Manner

Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS−/−), and STING-deficient (STINGgt/gt) mice to warm liver I/R injury and that found cGAS−/− mice had significantly increased liver injury compared with WT or STINGgt/gt mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS−/− mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS−/− hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. NEW & NOTEWORTHY Our studies are the first to document the important role of cGAS in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that cGAS protects liver from I/R injury in a STING-independent manner.

Development of New Small Molecule Bone Marrow Radioprotectors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4196-4196
Author(s):  
Yunyun Niu ◽  
Anthony J. Kanai ◽  
Peter Wipf ◽  
Xichen Zhang ◽  
Emily E. Greenberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Small Molecule ◽  
Ischemia Reperfusion Injury ◽  
Ethyl Pyruvate ◽  
Survival Curve ◽  
Ischemia Reperfusion ◽  
Irradiation Damage ◽  
Before And After ◽  
Nos Inhibitor

Abstract New ways to protect the bone marrow from irradiation damage are required. We are currently developing new small molecules that can be given orally to protect the marrow from irradiation damage. One small molecule is EUK-134, a manganese superoxide dismutase (MnSOD) mimetic. A nitric oxide synthase inhibitor, and a nitroxide homologue which have been both conjugated to a mitochondrial localization peptide signal, delivers the NOS inhibitor (another radioprotector) and nitroxide to the mitochondria. In addition, we tested ethyl pyruvate (EP), which has been demonstrated to protect tissues from ischemia-reperfusion injury at the level of the mitochondria. Incubation of 32D cl 3 hematopoietic cells 1 hour before irradiation in the presence of 20 μM EUK-134 or 100 μM of NOS inhibitor demonstrated an increased shoulder on the irradiation survival curve in one case (n = 5.55 ± 0.17 for EUK-134 compared to 1.60 ± 0.38 for control irradiated, respectively, p = 0.0044) and increase in the D0 for the mitochondrial targeted NOS inhibitor compared to irradiated control 32D cl 3 cells (D0 = 3.04 ± 0.27 compared to 1.29 ± 0.01 Gy, p = 0.0236). In experiments with 32D cl 3 cells in EP before irradiation or following irradiation, there was an increase in the D0 to 2.2 ± 0.25 and 2.21 ± 0.15, respectively, compared to irradiated controls 1.42 ± 0.09 Gy for the 32D cl 3 cells (p = 0.0447 and 0.0119, respectively). Furthermore, incubation of 32D cl 3 cells in EP both before and after irradiation significantly increased the shoulder on the survival curve compared to irradiated control 32D cl 3 cells (n = 4.14 ± 1.59 compared to 1.70 ± 0.6 for the control irradiated cells, respectively, p=0.0485). To determine whether EP protected the bone marrow from irradiation in vivo, C57BL/6J mice were injected with EP intraperitoneally (70 mg/kg) 30 minutes before irradiation, daily for 5 days after irradiation, or both before and following irradiation to the LD 50/30 TBI dose of 900 cGy. Mice injected with EP either after irradiation or both before and after irradiation had prolonged survival compared to irradiated control mice or those injected with EP only before irradiation. (Percent survival at 50 days 100% and 100%, respectively, compared to 60%, p&lt;0.05). These results demonstrate the potential effectiveness of new small molecule bone marrow radioprotectors.

scholarly journals Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO

2015 ◽  
Vol 112 (3) ◽  
pp. 899-904 ◽  
Author(s):  
Qiang Li ◽  
Ping Wang ◽  
Keqiang Ye ◽  
Hua Cai
Keyword(s):  
Ubiquitin Ligase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
E3 Ubiquitin Ligase ◽  
No Production ◽  
Deleted In Colorectal Cancer ◽  
Seven In Absentia ◽  
Deficient Mice

Deleted in colorectal cancer (DCC), a large transmembrane receptor of netrin-1, is critical for mediating netrin-1’s cardioprotective function. In the present study we investigated novel mechanisms underlying netrin-1–induced, rapid, and feed-forward up-regulation of DCC, which is believed to sustain nitric oxide (NO) production to potentiate cardioprotection. Intriguingly, NO markedly reduced expression of the E3 ubiquitin ligase seven in absentia homolog (SIAH) that is specific for regulation of protesome-dependent DCC degradation, resulting in accumulation of DCC. The two SIAH isoforms compensate for each other when one is repressed; inhibition of both SIAH1 and SIAH2 using combined siRNAs significantly reduced infarct size while improving cardiac function after ischemia/reperfusion injury of the heart. This effect was absent in DCC-deficient mice. Moreover, in vivo RNAi inhibition of SIAH1/2 further augmented netrin-1’s cardioprotective function. In summary, these data identify a novel therapeutic target of SIAH in facilitating NO/netrin-1–dependent cardioprotection, using the DCC receptor. Combination of netrin-1 and SIAH RNAi may prove to be a substantially effective therapy for myocardial infarction.

Interleukin 35 protects cardiomyocytes following ischemia/reperfusion-induced apoptosis via activation of mitochondrial STAT3

2021 ◽  
Author(s):  
Fengyun Zhou ◽  
Ting Feng ◽  
Xiangqi Lu ◽  
Huicheng Wang ◽  
Yangping Chen ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Cytochrome C Release ◽  
Neonatal Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Abstract Mitochondrial reactive oxygen species (mtROS)-induced apoptosis has been suggested to contribute to myocardial ischemia/reperfusion injury. Interleukin 35 (IL-35), a novel anti-inflammatory cytokine, has been shown to protect the myocardium and inhibit mtROS production. However, its effect on cardiomyocytes upon exposure to hypoxia/reoxygenation (H/R) damage has not yet been elucidated. The present study aimed to investigate the potential protective role and underlying mechanisms of IL-35 in H/R-induced mouse neonatal cardiomyocyte injury. Mouse neonatal cardiomyocytes were challenged to H/R in the presence of IL-35, and we found that IL-35 dose dependently promotes cell viability, diminishes mtROS, maintains mitochondrial membrane potential, and decreases the number of apoptotic cardiomyocytes. Meanwhile, IL-35 remarkably activates mitochondrial STAT3 (mitoSTAT3) signaling, inhibits cytochrome c release, and reduces apoptosis signaling. Furthermore, co-treatment of the cardiomyocytes with the STAT3 inhibitor AG490 abrogates the IL-35-induced cardioprotective effects. Our study identified the protective role of IL-35 in cardiomyocytes following H/R damage and revealed that IL-35 protects cardiomyocytes against mtROS-induced apoptosis through the mitoSTAT3 signaling pathway during H/R.

Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

2020 ◽  
Author(s):  
Kang Zhou ◽  
Yan Xu ◽  
Qiong Wang ◽  
Lini Dong
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Protective Role ◽  
Human Cardiomyocytes ◽  
Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

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