scholarly journals MiR-31 Downregulation Protects Against Cardiac Ischemia/Reperfusion Injury by Targeting Protein Kinase C Epsilon (PKCe) Directly

2015 ◽  
Vol 36 (1) ◽  
pp. 179-190 ◽  
Author(s):  
Yongyi Wang ◽  
Min Men ◽  
Wengang Yang ◽  
Hui Zheng ◽  
Song Xue
Keyword(s):  
Reperfusion Injury ◽  
Target Gene ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Cardioprotective Effect ◽  
Myocardial Infarct Size

Background: Various miRNAs have been shown to participate in cardiac ischemia/reperfusion injury (I/R). miR-31 was identified as the most strikingly upregulated miRNA after acute myocardial infarction; therefore, the underlying role and mechanism of miR-31 in cardiac I/R was investigated. Methods: miR-31 expression was detected after cardiac I/R in mice. The cardioprotective effect of miR-31 downregulation was assessed in vitro and in vivo. The functional target gene and its downstream molecule were determined. Results: miR-31 expression increased after I/R. miR-31 downregulation increased cell viability and SOD activity and decreased LDH activity and MDA content in vitro. Additionally, miR-31 downregulation alleviated myocardial infarct size in vivo. PKCe was identified as the functional target gene of miR-31, and NFκB was identified as its downstream molecule that was involved in the miR-31-mediated cardioprotective effect. Conclusion: miR-31 expression increased throughout the cardiac I/R process, and miR-31 downregulation induced a cardioprotective effect via a miR-31/PKCe/NFκB-dependent pathway.

scholarly journals Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Hai-Jing Sun ◽  
Yan Lu ◽  
Hao-Wei Wang ◽  
Hao Zhang ◽  
Shuang-Ran Wang ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Ischemia Reperfusion Injury ◽  
Culture Media ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
In Vivo Model ◽  
Myocardial Infarct Size ◽  
Cb2 Receptor

Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

scholarly journals Sp1 Targeted PARP1 Inhibition Protects Cardiomyocytes From Myocardial Ischemia–Reperfusion Injury via Downregulation of Autophagy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifeng Xu ◽  
Boqian Wang ◽  
Xiaoxiao Liu ◽  
Yunfei Deng ◽  
Yanqi Zhu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Target Gene ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.

scholarly journals Influence of ramiprilat and losartan on ischemia reperfusion injury in rat hearts

2011 ◽  
Vol 13 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Fatemeh Safari ◽  
Sohrab Hajizadeh ◽  
Shahnaz Shekarforoush ◽  
Gholamreza Bayat ◽  
Mohsen Foadoddini ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Saline Group ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Dependent Manner ◽  
Protective Effects

Hypothesis/introduction: Our aim was to investigate whether a non-hypotensive dose of ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo. Materials and methods: Three groups of rats were given 10 mg/kg per day of losartan for one (L-1W), four (L-4W) or 10 (L-10W) weeks. Another three groups were given 50 µg/kg per day of ramiprilat for one (R-1W), four (R-4W) or 10 (R-10W) weeks. The animals underwent 30 min of left anterior descending artery occlusion and subsequent reperfusion for 120 min. Results: Myocardial infarct size (IS) was reduced in R-1W (28.4 ± 6.3%, p < 0.001), R-4W (27.8 ± 7.4, p < 0.001), L-4W (31.8 ± 6%, p < 0.05) and L-10W (25.3 ± 5.7, p < 0.001) groups compared with a saline group (48.3 ± 7.8%). A significant reduction in the number of ventricular ectopic beats (VEBs) was noted in groups R-1W (209 ± 41, p < 0.01), R-4W (176 ± 39, p < 0.01), L-4W (215 ± 52, p < 0.05) and L-10W (191 ± 61, p < 0.01 vs. saline 329 ± 48). The incidence of irreversible ventricular fibrillation (VF) and mortality were decreased significantly only in L-10W group. There were no significant decreases in episodes of VT, the incidence of irreversible VF and mortality in all of the groups treated with ramiprilat. Conclusion: These data indicate that losartan and ramiprilat protect the heart against ischemia/reperfusion injury independently of their hemodynamic effects but in a time-dependent manner.

scholarly journals Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

2018 ◽  
Vol 45 (3) ◽  
pp. 883-898 ◽  
Author(s):  
Yinping Du ◽  
Ping Liu ◽  
Tongda Xu ◽  
Defeng Pan ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background/Aims: The myocardial sarcoplasmic reticulum calcium ATPase (SERCA2a) is a pivotal pump responsible for calcium cycling in cardiomyocytes. The present study investigated the effect of luteolin (Lut) on restoring SERCA2a protein level and stability reduced by myocardial ischemia/reperfusion (I/R) injury. We verified a hypothesis that Lut protected against myocardial I/R injury by regulating SERCA2a SUMOylation. Methods: The hemodynamic data, myocardial infarct size of intact hearts, apoptotic analysis, mitochondrial membrane potential (ΔΨm), the level of SERCA2a SUMOylation, and the activity and expression of SERCA2a were examined in vivo and in vitro to clarify the cardioprotective effects of Lut after SUMO1 was knocked down or over-expressed. The putative SUMO conjugation sites in mouse SERCA2a were investigated as the possible regulatory mechanism of Lut. Results: Initially, we found that Lut reversed the SUMOylation and stability of SERCA2a as well as the expression of SUMO1, which were reduced by I/R injury in vitro. Furthermore, Lut increased the expression and activity of SERCA2a partly through SUMO1, thus improving ΔΨm and reducing apoptotic cells in vitro and promoting the recovery of heart function and reducing infarct size in vivo. We also demonstrated that SUMO acceptor sites in mouse SERCA2a involving lysine 585, 480 and 571. Among the three acceptor sites, Lut enhanced SERCA2a stability via lysine 585. Conclusions: Our results suggest that Lut regulates SERCA2a through SUMOylation at lysine 585 to attenuate myocardial I/R injury.

Increased ROCK1 not ROCK2 in circulating leukocytes in rats with myocardial ischemia/reperfusion

Perfusion ◽  
2020 ◽  
Vol 35 (8) ◽  
pp. 819-825
Author(s):  
Chao Cheng ◽  
Xiao-Bo Liu ◽  
Dong-Ling Xu ◽  
Juan Zhang
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Rock Activity

Background: Rho-associated protein kinase (ROCK) plays a vital role in the pathogenesis of many cardiovascular diseases. Previous studies have demonstrated that ROCK is overactivated and involved in myocardial ischemia/reperfusion in vivo. But the role of ROCK in circulating leukocytes during myocardial ischemia/reperfusion is not well studied. Material and methods: This study was performed to evaluate ROCK activity in circulating leukocytes in rats with myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion Wistar rats were subjected to 30-min ischemia followed by 180-min reperfusion. ROCK activity in circulating leukocytes was examined by the phosphorylation state of myosin phosphatase targeting subunit 1, a substrate of ROCK. Results: ROCK activity significantly increased in leukocytes in rat ischemia/reperfusion models compared to the sham group. ROCK1 not ROCK2 level in circulating leukocytes was significantly elevated in ischemia/reperfusion. Administration of the selective inhibitor of ROCK, fasudil, significantly reduced myocardial infarct size, myocyte apoptosis, and inflammatory cytokine, including interleukin 6 and tumor necrosis factor α. Furthermore, fasudil upregulated ischemia/reperfusion-induced reduction of nitric oxide production. Conclusion: Increased ROCK1 not ROCK2 in circulating leukocytes plays a role in the pathogenesis of myocardial ischemia/reperfusion injury. Inhibition of ROCK1 in circulating leukocytes has an important role in fasudil-induced cardioprotective effects. ROCK1 in circulating leukocytes might be a new biomarker in myocardial ischemia/reperfusion injury.

scholarly journals N6-methyladenosine demethylase FTO impairs hepatic ischemia–reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ying Dong Du ◽  
Wen Yuan Guo ◽  
Cong Hui Han ◽  
Ying Wang ◽  
Xiao Song Chen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fragmentation ◽  
Hepatic Ischemia ◽  
Adeno Associated Virus ◽  
Downstream Target ◽  
Hepatic Ischemia Reperfusion

AbstractDespite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.

In vivo and In vitro PPAR-y Activation Decreases M1-Macrophage Polarization and Improves Liver Ischemia Reperfusion Injury

2018 ◽  
Vol 102 ◽  
pp. S708
Author(s):  
Ivan Linares ◽  
Agata Bartczak ◽  
Kaveh Farrokhi ◽  
Dagmar Kollmann ◽  
Moritz Kaths ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Liver Ischemia ◽  
M1 Macrophage

scholarly journals Poly-IC Preconditioning Protects against Cerebral and Renal Ischemia-Reperfusion Injury

2011 ◽  
Vol 32 (2) ◽  
pp. 242-247 ◽  
Author(s):  
Amy E B Packard ◽  
Jason C Hedges ◽  
Frances R Bahjat ◽  
Susan L Stevens ◽  
Michael J Conlin ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Cortical Cells ◽  
Polycytidylic Acid ◽  
Populations At Risk

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

scholarly journals Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation

2020 ◽  
Vol 31 (3) ◽  
pp. 517-531 ◽  
Author(s):  
Sistiana Aiello ◽  
Manuel Alfredo Podestà ◽  
Pamela Y. Rodriguez-Ordonez ◽  
Francesca Pezzuto ◽  
Nadia Azzollini ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Antigen Presentation ◽  
Kidney Transplant ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cold Ischemia ◽  
Reversible Ischemia ◽  
Antigen Presenting

BackgroundIn donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells.MethodsWe evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8–deficient donors.ResultsCold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8–deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses.ConclusionsIL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.

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