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 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.

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.

Abstract 16381: Novel Thiol-activated H2S Donors Attenuate Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Chelsea Organ ◽  
Zhen Li ◽  
Yu Zhao ◽  
Chuntao Yang ◽  
Shashi Bhushan ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Sustained Release ◽  
Murine Model ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background: Hydrogen sulfide (H2S) protects against acute myocardial ischemia/reperfusion (MI/R) injury and heart failure by ameliorating oxidative stress, improving mitochondrial function, and attenuating apoptosis. One of the major limitations of currently available H2S donors is poor pharmacokinetics profiles that result in very rapid and uncontrolled H2S release. NSHD-1 and NSHD-2 are recently developed thiol-activated H2S donors designed for sustained release of H2S upon activation by molecules containing thiol groups such as cysteine and glutathione. We hypothesized that these novel H2S donors would generate H2S for extended periods and ameliorate myocardial cell death following MI/R in an in vivo murine model. Methods and Results: C57BL6/J male mice (10-12 weeks of age) were subjected to 45 minutes of MI followed by 24 hours of R. At the time of reperfusion, animals received Vehicle (0.5% THF), NSHD-1 (50 μg/kg and 100 μg/kg), or NSHD-2 (50 μg/kg) by direct intracardiac (i.c.) injection. In addition, at 4 hours of R, plasma was collected for troponin-I measurements. In preliminary studies we observed sustained release of H2S with both of these H2S donors. Myocardial infarct size was reduced by 35% (p < 0.01 vs. Vehicle) in mice treated with NSHD-1 (100 μg/kg), 43% (p < 0.05 vs. Vehicle) in mice treated with NSHD-2 (50 μg/kg), and 54% (p < 0.01 vs. Vehicle) in mice treated with NSHD-2 (100 μg/kg). Conclusions: NSHD-1 and NSHD-2 significantly attenuate MI/R injury in a murine model. Experiments are currently underway to further define the in vivo pharmacokinetics of H2S release from these agents, mechanisms of action, and safety profile.

scholarly journals Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Changsheng Nai ◽  
Haochen Xuan ◽  
Yingying Zhang ◽  
Mengxiao Shen ◽  
Tongda Xu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Signaling Pathway ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Myocardial Infarct Size ◽  
Akt Signaling Pathway ◽  
Cardioprotective Effects

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.

scholarly journals miR-19a/b-3p promotes inflammation during cerebral ischemia/reperfusion injury via SIRT1/FoxO3/SPHK1 pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Feng Zhou ◽  
Yu-Kai Wang ◽  
Cheng-Guo Zhang ◽  
Bing-Yi Wu
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Luciferase Assay ◽  
In Vivo Model ◽  
Tunel Staining

Abstract Background Stroke affects 3–4% of adults and kills numerous people each year. Recovering blood flow with minimal reperfusion-induced injury is crucial. However, the mechanisms underlying reperfusion-induced injury, particularly inflammation, are not well understood. Here, we investigated the function of miR-19a/b-3p/SIRT1/FoxO3/SPHK1 axis in ischemia/reperfusion (I/R). Methods MCAO (middle cerebral artery occlusion) reperfusion rat model was used as the in vivo model of I/R. Cultured neuronal cells subjected to OGD/R (oxygen glucose deprivation/reperfusion) were used as the in vitro model of I/R. MTT assay was used to assess cell viability and TUNEL staining was used to measure cell apoptosis. H&E staining was employed to examine cell morphology. qRT-PCR and western blot were performed to determine levels of miR-19a/b-3p, SIRT1, FoxO3, SPHK1, NF-κB p65, and cytokines like TNF-α, IL-6, and IL-1β. EMSA and ChIP were performed to validate the interaction of FoxO3 with SPHK1 promoter. Dual luciferase assay and RIP were used to verify the binding of miR-19a/b-3p with SIRT1 mRNA. Results miR-19a/b-3p, FoxO3, SPHK1, NF-κB p65, and cytokines were elevated while SIRT1 was reduced in brain tissues following MCAO/reperfusion or in cells upon OGD/R. Knockdown of SPHK1 or FoxO3 suppressed I/R-induced inflammation and cell death. Furthermore, knockdown of FoxO3 reversed the effects of SIRT1 knockdown. Inhibition of the miR-19a/b-3p suppressed inflammation and this suppression was blocked by SIRT1 knockdown. FoxO3 bound SPHK1 promoter and activated its transcription. miR-19a/b-3p directly targeted SIRT1 mRNA. Conclusion miR-19a/b-3p promotes inflammatory responses during I/R via targeting SIRT1/FoxO3/SPHK1 axis.

Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury

1998 ◽  
Vol 275 (5) ◽  
pp. H1865-H1872 ◽  
Author(s):  
Anthony J. Palazzo ◽  
Steven P. Jones ◽  
Donald C. Anderson ◽  
D. Neil Granger ◽  
David J. Lefer
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia Reperfusion

We investigated in vivo coronary P-selectin expression and its pathophysiological consequences in a murine model of myocardial ischemia-reperfusion (MI/R) using wild-type and P-selectin deficient (−/−) mice. Coronary P-selectin expression [μg monoclonal antibody (MAb)/g tissue] was measured using a radiolabeled MAb method after 30 min of myocardial ischemia and 20 min of reperfusion. P-selectin expression in wild-type mice was significantly ( P< 0.01) elevated in the ischemic zone (0.070 ± 0.010) compared with the nonischemic zone (0.037 ± 0.008). Myocardial P-selectin expression was nearly undetectable in P-selectin −/− mice after MI/R. Furthermore, myocardial infarct size (% of area at risk) after 30 min of myocardial ischemia and 120 min of reperfusion was 42.5 ± 4.4 in wild-type mice and 24.4 ± 4.0 in P-selectin −/− mice ( P < 0.05). In additional experiments of prolonged myocardial ischemia (60 min) and reperfusion (120 min), myocardial infarct size was similar in P-selectin −/− mice and wild-type mice. Our results clearly demonstrate the involvement of coronary P-selectin in the development of myocardial infarction after MI/R.

Loss of Sema4D Signaling in Platelets Impairs the Formation and Stability of Arterial Thrombi In Vivo and Reduces Myocardial Infarct Size.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3631-3631 ◽  
Author(s):  
Li Zhu ◽  
Timothy J. Stalker ◽  
Tao Wang ◽  
Hong Jiang ◽  
Atushi Kumanogoh ◽  
...  
Keyword(s):  
Infarct Size ◽  
Platelet Function ◽  
Ischemia Reperfusion Injury ◽  
Thrombus Formation ◽  
Infarct Volume ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Cremaster Muscle

Abstract Contact-dependent signaling between platelets helps to promote thrombus growth and stability. One mechanism for contact-dependent signaling involves the binding of cell surface ligands to corresponding receptors on the surface of adjacent cells. In our efforts to identify novel participants in this process, we have recently reported that platelets express on their surface the semaphorin family member, sema4D, and its two known receptors, CD72 and plexin-B1 (Zhu, et al, PNAS, 2007). We have also shown that although their initial tail bleeding time is normal, platelets from sema4D(−/−) mice have a defect in collagen-induced signaling and platelet aggregation in vitro. In the present studies, we used matched sema4D(−/−) and wild type (WT) mice to examine the consequences of impaired sema4D signaling in models of platelet function in vivo. In the first model, irradiated Rose Bengal dye was used to produce an arteriolar injury in an exteriorized cremaster muscle. Platelets were identified with a fluorescent CD41 antibody and detected in real time using digital microscopy. The results showed that thrombus formation occurred in all of the mice that were tested, but while stable occlusion was observed in approximately half of the control mice, none of the sema4D(−/−) mice developed stable occlusions during the period of observation (p&lt;0.02). Similarly, when a laser was used to produce a focal injury in cremaster muscle arterioles, both the initial rate of platelet accumulation and the peak extent of accumulation were approximately 50% lower in the sema4D(−/−) mice than in the matched controls. To test the contribution of sema4D to platelet responses in a larger artery, the right common carotid was injured by transient exposure to FeCl3 and changes in flow were measured using a Doppler probe. The results showed that the time to occlusion was 35% greater in the sema4D(−/−) mice than in controls (p&lt;0.02). Furthermore, stable occlusion occurred in only 9 of 16 (56%) sema4D(−/−) mice Vs. 7 of 9 (78%) WT mice. Finally, myocardial infarct size was measured in an ischemia/reperfusion injury model 48 hrs after transient ligation of the left anterior descending coronary artery. Although infarction occurred in all cases, infarct volume was 56% smaller in the sema4D(−/−) mice than the matched controls (p&lt;0.01). In summary, these results show that there is a substantial impairment of platelet function in vivo in mice that lack sema4D. This impairment was observed in both arterioles and arteries using several different methods to evoke platelet activation. When combined with our earlier observations, the results show that signaling by sema4D and its receptors provides a novel mechanism to promote thrombus growth and stability.

Abstract 3878: Glucagon-Like Peptide-1 Metabolite Protects the Myocardium Against Ischemia-Reperfusion Injury in Diabetes Mellitus

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Susheel Gundewar ◽  
John W Elrod ◽  
John W Calvert ◽  
Xuelaing Du ◽  
Diane Edelstein ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Diabetic Mice ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background: Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone with potent plasma glucose lowering actions that is rapidly degraded by the enzyme Dipeptidyl Peptidase-IV to GLP-1(9 –36) amide . GLP-1(9 –36) amide (GLP1dp) has previously been viewed to be biologically inactive. However, our laboratory has demonstrated that GLP1dp inhibits hyperglycemia-induced production of oxidant species and prevents the inactivation of both eNOS and prostacyclin synthase in cells and diabetic animals. We investigated the effects of GLP1dp in two in vivo diabetic murine models of myocardial ischemia-reperfusion (MI-R) injury. Methods: Diabetic (db/db and STZ-diabetic) mice were treated with 2.4 μg/day of GLP1dp via Alzet pump for 7 days and subjected to 45 min of left coronary artery occlusion and 2 hr of R. At 2 hr of R, hearts were excised and evaluated for infarct (INF) size. Results: Diabetic (db/db) and STZ-diabetic mice treated with GLP1dp exhibited a 37% and 33% reduction in myocardial infarct size following MI-R respectively. Additionally, GLP1dp significantly reduced oxidative stress in the myocardium of these mice. Both models of diabetic mice (db/db and STZ-diabetic) exhibited elevated baseline blood glucose (BG) values of 386 ± 25 and 435 ± 15 mg/dl respectively. After 7 days of GLP1dp therapy, db/db mice exhibited a 48% reduction in BG values. In contrast, no reduction in BG was observed in the STZ-diabetic mice. Conclusion : Administration of GLP1dp peptide confers cardioprotection in diabetic mice by attenuating the extent of oxidant-mediated injury following MI-R. The cardioprotective actions of GLP1dp appear to be independent of any effects on blood glucose.

Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction

2007 ◽  
Vol 293 (4) ◽  
pp. H2418-H2428 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Anuradha Kalyanasundaram ◽  
Xue Zhao ◽  
Li Zuo ◽  
Poornima Bhupathy ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Salvage ◽  
Myocardial Infarct Size ◽  
Intracellular Ca ◽  
Developed Pressure

Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca2+ overload with reduced activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular Ca2+ homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster Ca2+ transport kinetics. Therefore, to further address this issue and to evaluate whether SERCA1a expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCA1a transgenic (SERCA1a+/+) and nontransgenic (NTG) mice. Langendorff-perfused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in SERCA1a+/+ mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, SERCA1a+/+ hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed better-preserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in SERCA1a+/+ hearts. Importantly, intraischemic Ca2+ levels were significantly lower in SERCA1a+/+ hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus SERCA1a+/+ hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic Ca2+ overload and thus provides potent myocardial protection.

scholarly journals IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Sandrine Lecour ◽  
Ioanna Andreadou ◽  
Hans Erik Bøtker ◽  
Sean M. Davidson ◽  
Gerd Heusch ◽  
...  
Keyword(s):  
Animal Studies ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Therapeutic Interventions ◽  
Acute Ischemia ◽  
Myocardial Infarct Size ◽  
Patient Benefit ◽  
The Eu

AbstractAcute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.

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