scholarly journals Resolvin D1 inhibits endothelial permeability and mitochondrial damage following cardiac ischemia reperfusion in diabetic mice

2021 ◽  
Author(s):  
Jialiang Zhang ◽  
Fangyang Huang ◽  
Li Chen ◽  
Guoyong Li ◽  
Dan Xiao ◽  
...  
Keyword(s):  
Infarct Size ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
Mitochondrial Damage ◽  
Diabetic Mice ◽  
Resolvin D1

Abstract Purpose Novel strategies for preventing myocardial ischemia reperfusion injury (MIRI) in a diabetic heart are urgently needed. Resolvin D1 (RvD1) plays important therapeutic roles in inflammatory diseases. However, the therapeutic role of RvD1 in diabetic MIRI is still unknown. Methods Diabetic mice were established with a high-fat diet and streptozotocin (STZ). The mice were pretreated with RvD1 via intraperitoneal injection for 3 days, followed by MIRI. To evaluate the effects of RvD1 on chronic cardiac remodelling, RvD1 was administered for another 2 weeks after MIRI. The effects of RvD1 following MIRI were measured, including the severity of infarct size, regional inflammation, cardiac function, and permeability of cultured endothelial monolayers. Mitochondrial reactive oxygen species (MitoROS) and mitochondrial membrane potential (MMP) were determined using MitoSOX and JC-1. Results RvD1 pretreatment significantly reduced infarct size and the Evans blue content in diabetic injured hearts, which was associated with improved endothelial permeability. At 2 weeks after MIRI, RvD1 treatment partially improved cardiac performance and reduced cardiac fibrosis in diabetic MIRI mice. In vitro, RvD1 attenuated endothelial leakage induced by hypoxia-reoxygenation, H2O2, and lipopolysaccharide (LPS) under high glucose (HG) conditions. Meanwhile, RvD1 remarkably protected endothelial cells from H2O2-induced mitochondrial damage, as evidenced by increased MMP and decreased MitoROS, which was associated with the preservation of VE-cadherin. Conclusion RvD1 alleviates MIRI-induced endothelial permeability and mitochondrial damage injuries in diabetic hearts. Therefore, RvD1 could be a potential therapeutic target for MIRI in diabetes.

scholarly journals Resolvin D1 Inhibits Endothelial Permeability and Mitochondrial Damage Following Cardiac Ischemia–Reperfusion in Diabetic Mice

2021 ◽  
Author(s):  
Jialiang Zhang ◽  
Fangyang Huang ◽  
Li Chen ◽  
Guoyong Li ◽  
Dan Xiao ◽  
...  
Keyword(s):  
Infarct Size ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
Endothelial Damage ◽  
Mitochondrial Damage ◽  
Control Group ◽  
Diabetic Mice ◽  
Resolvin D1

Abstract Purpose Resolvin D1(RvD1), a metabolite derived from docosahexaenoic acid, plays important therapeutic roles in inflammatory diseases. However, the role of RvD1 in diabetic myocardial ischemia/reperfusion (IR) is still unknown. Methods Diabetic mice was established by high-fat diet and streptozotocin, RvD1 was pretreated by intraperitoneal injection for 3 days, followed by myocardial IR. To evaluate the effects of RvD1 on chronic cardiac remodeling, RvD1 was administered for another 2 weeks after IR. The effects of RvD1 following myocardial IR injury were measured, including severity of infarct size, regional inflammation, cardiac function, as well as permeability of cultured endothelial monolayer. Mitochondrial reactive oxygen species (mito-ROS) and mitochondrial membrane potential (MMP) were determined by MitoSOX and JC-1. Results RvD1 pretreatment significantly reduced infarct size and the content of Evans blue in injured heart, which was associated with decreased endothelial damage. RvD1 also reduced leukocyte density, gene expression of inflammatory cytokines, cardiomyocytes death, and mitochondrial damage compared to control group. At 2 weeks after myocardial IR, RvD1 treatment partially improved cardiac performance, and reduced cardiac fibrosis in diabetic IR. In vitro, RvD1 attenuated endothelial leakage induced by hypoxia-reoxygenation, H2O2, and Lipopolysaccharide (LPS), meanwhile, RvD1 also remarkably protected endothelial cells from H2O2-induced mitochondrial damage as evident from the decreased MMP and increased mito-ROS, which were associated with the preservation of VE-cadherin Conclusion RvD1 protects the heart against diabetic IR-induced injuries by attenuating endothelial permeability and mitochondrial damage. Our study also provide insight into a novel underlying mechanism and a new strategy for treating diabetic IR.

Abstract 782: Fra2 Mediates Oxygen-induced TGFbeta-1 mRNA Expression In Adult Cardiac Fibroblasts: Significance In Myocardial Fibrosis Following Ischemia-reperfusion Injury

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Sashwati Roy ◽  
Savita Khanna ◽  
Chandan K Sen
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter ◽  
Mrna Levels

Background . Transforming growth factor beta-1 (TGFbeta-1) is a key cytokine implicated in the development of cardiac fibrosis following ischemia-reperfusion (IR) injury. The profibrotic effects of TGFbeta-1 are primarily attributable to the differentiation of cardiac fibroblasts (CF) to myofibroblasts. Previously, we have reported perceived hyperoxia (Circ Res 92:264 –71), sub-lethal reoxygenation shock during IR, induces differentiation of CF to myofibroblasts at the infarct site. The mechanisms underlying oxygen-sensitive induction of TGFbeta-1 mRNA remain to be characterized. Hypothesis . Fra2 mediates oxygen-induced TGFbeta-1 mRNA expression in adult cardiac fibroblasts. Methods. TGFbeta-1 mRNA expression in infarct tissue was investigated in an IR injury model. The left anterior descending coronary artery of mice was transiently occluded for 60 minutes followed by reperfusion to induce IR injury. Spatially resolved infarct and non-infarct tissues were collected at 0, 1, 3, 5, and 7 days post-IR using laser capture microdissection. TGFbeta-1 mRNA levels were measured using real-time PCR. To investigate the role of oxygen in the regulation of TGFbeta-1, we used our previously reported model of perceived hyperoxia where CF (from 5wks old mice) after isolation were cultured at 5%O 2 (physiological pO 2 ) followed by transferring them to 20%O 2 to induce hyperoxic insult. Results & Conclusions. In vivo, a significant increase (p<0.01; n=5) in TGFbeta-1 mRNA was observed at the infarct site already at day 1 post-IR. The levels continued to increase until day 7 post-IR. In vitro, exposure of CF to 20%O 2 hyperoxic insult induced TGFbeta-1 mRNA (p<0.001; n=4) and protein (p<0.01; n=4) expression. Using a TGFbeta-1 promoter-luciferase reporter and DNA binding assays, we collected first evidence that AP-1 and its component Fra2 as major mediators of oxygen-induced TGFbeta-1 expression. Exposure to 20%O 2 resulted in increased localization of Fra2 in nucleus. siRNA-dependent Fra-2 knock-down completely abrogated oxygen-induced TGFbeta1 expression. In conclusion, this study presents first evidence that Fra-2 is involved in inducible TGFbeta1 expression in CF. Fra2 was noted as being central in regulating oxygen-induced TGFbeta-1 expression.s

The Synthetic Pentasaccharide, Fondaparinux, Reduces Inflammation and Neutrophil Accumulation in Kidney Ischemia-Reperfusion Injury.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 217-217 ◽  
Author(s):  
Gernot Schabbauer ◽  
Rolf D. Frank ◽  
Todd Holscher ◽  
Yuichiro Sato ◽  
Michael Tencati ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Inflammatory Diseases ◽  
Anticoagulant Activity ◽  
Ischemia Reperfusion ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Inflammatory Cells ◽  
Neutrophil Accumulation ◽  
Kidney Ischemia

Abstract Acute inflammatory diseases are often accompanied by coagulation activation leading to local thrombotic complications and disseminated intravascular coagulation. Recent studies support the concept of crosstalk between coagulation and inflammation. The synthetic pentasaccharide, fondaparinux, is a selective antithrombin-dependent inhibitor of coagulation factor Xa. In this study, we investigated the effect of fondaparinux in a lethal murine model of kidney ischemia-reperfusion (I/R) injury that is associated with coagulation and inflammation. Fondaparinux treatment of I/R-injured mice significantly reduced serum creatinine levels and increased survival from 0 to 44% compared with saline treated control mice. In contrast, depletion of fibrinogen with ancrod was not protective, suggesting that fondaparinux may have additional properties beyond its anticoagulant activity. Indeed, fondaparinux significantly reduced IL-6 and MIP-2 expression but did not reduce MCP-1 expression. Furthermore, fondaparinux significantly decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced recruitment of neutrophils into the peritoneum in a model of acute peritonitis and inhibited the binding of U937 cells to P-selectin in vitro. Our data indicate that fondaparinux has both anticoagulant and anti-inflammatory activity reducing fibrin deposition and blocking the binding of inflammatory cells to activated endothelium. Fondaparinux may be useful in the treatment of acute inflammatory diseases.

Abstract 15884: Cardiosphere-Derived Cells Confer Acute Cardioprotection Following Ischemia-Reperfusion Injury in Rats: Role of Macrophage Polarization

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Geoffrey de Couto ◽  
Hideaki Kanazawa ◽  
Eleni Tseliou ◽  
Linda Marbán ◽  
Eduardo Marbán
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Oxidant Stress ◽  
Gene Profiles ◽  
Wistar Kyoto ◽  
Inflammatory Response To Injury

Introduction: Cardiosphere-derived cells (CDCs) confer both cardioprotection and regeneration in acute myocardial infarction (MI). However, only long-term (>3 wks) post-MI endpoints have been studied, making it impossible to investigate the cardioprotective effects in isolation. Macrophages (MF) concentrate within the heart following ischemic injury as part of the inflammatory response to injury. Here we test the hypothesis that CDCs are cardioprotective by modifying MF within the myocardium post-MI. Methods & Results: Wistar-Kyoto rats (aged 8-12 wks) underwent 45 min of ischemia followed by 20 min of reperfusion, then intracoronary (i.c.) infusion of either saline or CDCs (5x10 5 ). The use of a 48 hr endpoint enabled the selective study of cardioprotection. CDC-treated animals had preserved ejection fraction (59.2% vs. 47.4%; p<0.001) and reduced infarct size (TTC; 6.3% vs. 13.6%; p<0.01). The finding that CDC-treated hearts contained fewer CD68 + MF (p<0.05) suggested a mechanistic role for MF, a conjecture which we tested in detail. MF isolated from CDC-treated hearts secreted lower amounts of proinflammatory cytokines ( Nos2, Tnf, Il1b ; p<0.05). Systemic depletion of MF with clodronate liposomes attenuated the benefits of CDC therapy post-MI (p<0.05). In vitro , MF conditioned by transwell exposure to CDCs (M CDC ) exhibited distinct gene profiles relative to proinflammatory M 1 or “healing” M 2 polarization states (M CDC : Il10 ; M 1 : Nos2 ; M 2 : Arg1, Pparg ). Adoptive transfer of selective MF populations into the heart (i.c.; 20 min post-reflow) revealed that M CDC , but not M 1 or M 2 MF, could recapitulate the reduction in infarct size (M CDC : 4.5%; M 1 : 14.0%; M 2 : 10.8%; p<0.05). In vitro co-culture shows that M CDC selectively reduce cardiomyocyte apoptosis following oxidant stress (M CDC : 9.9%; M 1 : 39.4%; M 2 : 37.4%; p<0.001). Conclusions: CDCs are cardioprotective when administered 20 min after reflow; the timing distinguishes this form of cardioprotection from preconditioning or ischemic postconditioning. Various lines of evidence indicate that CDCs work by polarizing MF toward a cardioprotective phenotype. The findings motivate further translational development of the adjunctive use of CDCs post-MI to limit infarct size.

Autotaxin inhibition attenuates endothelial permeability after ischemia-reperfusion injury

2020 ◽  
Vol 75 (4) ◽  
pp. 399-407
Author(s):  
Aaron Strumwasser ◽  
Caitlin M. Cohan ◽  
Genna Beattie ◽  
Vincent Chong ◽  
Gregory P. Victorino
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
Hydraulic Permeability ◽  
Dependent Manner ◽  
Endothelial Monolayer ◽  
Monolayer Permeability

BACKGROUND: Autotaxin (ATX-secretory lysophospholipase D) is the primary lysophosphatidic acid (LPA) producing enzyme. LPA promotes endothelial hyper-permeability and microvascular dysfunction following cellular stress. OBJECTIVE: We sought to assess whether ATX inhibition would attenuate endothelial monolayer permeability after anoxia-reoxygenation (A-R) in vitro and attenuate the increase in hydraulic permeability observed after ischemia-reperfusion injury (IRI) in vivo. METHODS: A permeability assay assessed bovine endothelial monolayer permeability during anoxia-reoxygenation with/without administration of pipedimic acid, a specific inhibitor of ATX, administered either pre-anoxia or post-anoxia. Hydraulic permeability (Lp) of rat mesenteric post-capillary venules was evaluated after IRI, with and without ATX inhibition. Lastly, Lp was evaluated after the administration of ATX alone. RESULTS: Anoxia-reoxygenation increased monolayer permeability 4-fold (p < 0.01). Monolayer permeability was reduced to baseline similarly in both the pre-anoxia and post-anoxia ATX inhibition groups (each p < 0.01, respectively). Lp was attenuated by 24% with ATX inhibition (p < 0.01). ATX increased Lp from baseline in a dose dependent manner (p < 0.05). CONCLUSIONS: Autotaxin inhibition attenuated increases in endothelial monolayer permeability during A-R in vitro and hydraulic permeability during IRI in vivo. Targeting ATX may be especially beneficial by limiting its downstream mediators that contribute to mechanisms associated with endothelial permeability. ATX inhibitors may therefore have potential for pharmacotherapy during IRI.

scholarly journals Intravenous Sphingosylphosphorylcholine Protects Ischemic and Postischemic Myocardial Tissue in a Mouse Model of Myocardial Ischemia/Reperfusion Injury

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Christine Herzog ◽  
Martina Schmitz ◽  
Bodo Levkau ◽  
Ilka Herrgott ◽  
Jan Mersmann ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Mouse Model ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Polymorphonuclear Neutrophil ◽  
Myocardial Ischemia Reperfusion

HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. We therefore examined if HDL-associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL.In vitro, SPC inhibited leukocyte adhesion to TNFα-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injuryin vivovia the S1P3receptor.

scholarly journals Inhibition of Smurf2 translation by miR-322/503 protects from ischemia-reperfusion injury by modulating EZH2/Akt/GSK3β signaling

2019 ◽  
Vol 317 (2) ◽  
pp. C253-C261 ◽  
Author(s):  
Wei Dong ◽  
Fei Xie ◽  
Xuan-Ying Chen ◽  
Wei-Lin Huang ◽  
Yu-Zhen Zhang ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Terminal Deoxynucleotidyl Transferase ◽  
In Vivo Model ◽  
Tunel Staining ◽  
Triphenyltetrazolium Chloride ◽  
Perfused Heart

Myocardial ischemia-reperfusion (I/R) is a common and lethal disease that threatens people’s life worldwide. The underlying mechanisms are under intensive study and yet remain unclear. Here, we explored the function of miR-322/503 in myocardial I/R injury. We used isolated rat perfused heart as an in vivo model and H9c2 cells subjected with the oxygen and glucose deprivation followed by reperfusion as in vitro model to study myocardial I/R injury. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to measure the infarct size, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label (TUNEL) staining was used to examine apoptosis. Quantitative RT-PCR and Western blot were used to determine expression levels of miR-322/503, Smad ubiquitin regulatory factor 2 (Smurf2), enhancer of zeste homolog 2 (EZH2), p-Akt, and p-GSK3β. Overexpression of miR-322/503 decreased infarct size, inhibited cell apoptosis, and promoted cell proliferation through upregualtion of p-Akt and p-GSK3β. Thus the expression of miR-322/503 was reduced during I/R process. On the molecular level, miR-322/503 directly bound Smurf2 mRNA and suppressed its translation. Smurf2 ubiquitinated EZH2 and degraded EZH2, which could activate Akt/GSK3β signaling. Our study demonstrates that miR-322/503 plays a beneficial role in myocardial I/R injury. By inhibition of Smurf2 translation, miR-322/503 induces EZH2 expression and activates Akt/GSK3β pathway, thereby protecting cells from ischemia reperfusion injury.

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.

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