scholarly journals Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration

2019 ◽  
Vol 20 (3) ◽  
pp. 468 ◽  
Author(s):  
Alessandra Ciullo ◽  
Vanessa Biemmi ◽  
Giuseppina Milano ◽  
Sara Bolis ◽  
Elisabetta Cervio ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Systemic Administration ◽  
Systemic Delivery ◽  
Cxcr4 Antagonist ◽  
Intramyocardial Injection ◽  
Vitro Effect

Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of ExoCXCR4 significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to ExoCTRL (p < 0.01). Hemodynamic measurements showed that ExoCXCR4 improved dp/dt min, as compared to ExoCTRL and PBS group. In vitro, ExoCXCR4 was more bioactive than ExoCTRL in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.

scholarly journals Assessing the Efficacy of Dietary Selenomethionine Supplementation in the Setting of Cardiac Ischemia/Reperfusion Injury

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 546 ◽  
Author(s):  
Leila Reyes ◽  
David P. Bishop ◽  
Clare L. Hawkins ◽  
Benjamin S. Rayner
Keyword(s):  
Cardiac Myocyte ◽  
Hypochlorous Acid ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Cytosolic Calcium ◽  
Cardiac Ischemia ◽  
Cellular Damage

Oxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury. This partly arises from the presence of activated phagocytes releasing myeloperoxidase (MPO) and its production of hypochlorous acid (HOCl). The dietary supplement selenomethionine (SeMet) has been shown to bolster endogenous antioxidant processes as well as readily react with MPO-derived oxidants. The aim of this study was to assess whether supplementation with SeMet could modulate the extent of cellular damage observed in an in vitro cardiac myocyte model exposed to (patho)-physiological levels of HOCl and an in vivo rat model of cardiac I/R injury. Exposure of the H9c2 cardiac myoblast cell line to HOCl resulted in a dose-dependent increase in necrotic cell death, which could be prevented by SeMet supplementation and was attributed to SeMet preventing the HOCl-induced loss of mitochondrial inner trans-membrane potential, and the associated cytosolic calcium accumulation. This protection was credited primarily to the direct oxidant scavenging ability of SeMet, with a minor contribution arising from the ability of SeMet to bolster cardiac myoblast glutathione peroxidase (GPx) activity. In vivo, a significant increase in selenium levels in the plasma and heart tissue were seen in male Wistar rats fed a diet supplemented with 2 mg kg−1 SeMet compared to controls. However, SeMet-supplementation demonstrated only limited improvement in heart function and did not result in better heart remodelling following I/R injury. These data indicate that SeMet supplementation is of potential benefit within pathological settings where excessive HOCl is known to be generated but has limited efficacy as a therapeutic agent for the treatment of heart attack.

scholarly journals Naringenin Attenuates Myocardial Ischemia-Reperfusion Injury via cGMP-PKGIα Signaling and In Vivo and In Vitro Studies

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Li-Ming Yu ◽  
Xue Dong ◽  
Jian Zhang ◽  
Zhi Li ◽  
Xiao-Dong Xue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Er Stress ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Guanosine Monophosphate ◽  
Myocardial Ischemia Reperfusion

Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin’s inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.

scholarly journals Protective Effects of Polyphenols against Ischemia/Reperfusion Injury

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3469
Author(s):  
Martina Cebova ◽  
Olga Pechanova
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Radical Scavenging ◽  
Myocardial Necrosis ◽  
Protective Effects ◽  
Natural Polyphenols ◽  
Tissue Degeneration ◽  
Heart Contractility

Myocardial infarction (MI) is a leading cause of morbidity and mortality across the world. It manifests as an imbalance between blood demand and blood delivery in the myocardium, which leads to cardiac ischemia and myocardial necrosis. While it is not easy to identify the first pathogenic cause of MI, the consequences are characterized by ischemia, chronic inflammation, and tissue degeneration. A poor MI prognosis is associated with extensive cardiac remodeling. A loss of viable cardiomyocytes is replaced with fibrosis, which reduces heart contractility and heart function. Recent advances have given rise to the concept of natural polyphenols. These bioactive compounds have been studied for their pharmacological properties and have proven successful in the treatment of cardiovascular diseases. Studies have focused on their various bioactivities, such as their antioxidant and anti-inflammatory effects and free radical scavenging. In this review, we summarized the effects and benefits of polyphenols on the cardiovascular injury, particularly on the treatment of myocardial infarction in animal and human studies.

scholarly journals Non-coding RNAs modulate autophagy in myocardial ischemia-reperfusion injury: a systematic review

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Fuwen Huang ◽  
Jingting Mai ◽  
Jingwei Chen ◽  
Yinying He ◽  
Xiaojun Chen
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Diseases ◽  
Myocardial Ischemia ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Circular Rnas ◽  
Non Coding Rnas ◽  
Myocardial Ischemia Reperfusion

AbstractThe myocardial infarction is the main cause of morbidity and mortality in cardiovascular diseases around the world. Although the timely and complete reperfusion via Percutaneous Coronary Intervention (PCI) or thrombolysis have distinctly decreased the mortality of myocardial infarction, reperfusion itself may lead to supererogatory irreversible myocardial injury and heart function disorders, namely ischemia-reperfusion (I/R) injury. Extensive studies have indicated that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play important roles in the progress of myocardial I/R injury, which is closely correlative with cardiomyocytes autophagy. Moreover, autophagy plays an important role in maintaining homeostasis and protecting cells in the myocardial ischemia reperfusion and cardiomyocyte hypoxia-reoxygenation (H/R) progress. In this review, we first introduced the biogenesis and functions of ncRNAs, and subsequently summarized the roles and relevant molecular mechanisms of ncRNAs regulating autophagy in myocardial I/R injury. We hope that this review in addition to develop a better understanding of the physiological and pathological roles of ncRNAs, can also lay a foundation for the therapies of myocardial I/R injury, and even for other related cardiovascular diseases.

scholarly journals Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Juho Heliste ◽  
Anne Jokilammi ◽  
Katri Vaparanta ◽  
Ilkka Paatero ◽  
Klaus Elenius
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Potential Candidate ◽  
Egfr Inhibition ◽  
Shrna Library

AbstractThe return of blood flow to ischemic heart after myocardial infarction causes ischemia–reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia–reperfusion injury. Here we screened for targets for the treatment of ischemia–reperfusion injury using a combination of shRNA and drug library analyses in HL-1 mouse cardiomyocytes subjected to hypoxia and reoxygenation. The shRNA library included lentiviral constructs targeting 4625 genes and the drug library 689 chemical compounds approved by the Food and Drug Administration (FDA). Data were analyzed using protein–protein interaction and pathway analyses. EGFR inhibition was identified as a cardioprotective mechanism in both approaches. Inhibition of EGFR kinase activity with gefitinib improved cardiomyocyte viability in vitro. In addition, gefitinib preserved cardiac contractility in zebrafish embryos exposed to hypoxia-reoxygenation in vivo. These findings indicate that the EGFR inhibitor gefitinib is a potential candidate for further studies of repurposing the drug for the treatment of myocardial infarction.

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 Long noncoding RNA MALAT1 promotes cardiomyocyte apoptosis after myocardial infarction via targeting miR-144-3p

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Xiaohong Gong ◽  
Yun Zhu ◽  
Haixia Chang ◽  
Yongqin Li ◽  
Feng Ma
Keyword(s):  
Myocardial Infarction ◽  
Noncoding Rna ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Myocardial Apoptosis ◽  
Injury Model

AbstractOur study aims to excavate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in myocardial infarction (MI), especially in an ischemia/reperfusion injury model and the underlying mechanism involving the MALAT1-miR144 axis. Our results demonstrated that the expression of MALAT1 has a higher level, while miR-144 expression significantly reduced in myocardial tissue after MI and also in left anterior descending (LAD)-ligation mice. This result was confirmed in vitro studies in HL-1 cardiomyocytes followed with hypoxia/reoxygenation. In addition, overexpression of MALAT1 by MALAT1-pcDNA injection into the mice with LAD increased myocardial apoptosis in vivo, while this effect was attenuated by miR-144 mimic. Bioinformatics analysis exhibits that 3′-UTR of MALAT1 is targeted to the miR-144-3p. Up-regulation miR-144 blunted the hypoxia- or MALAT1-induced cell apoptosis. In conclusion, the expression of MALAT1 was increased, whereas miR-144 expression was down-regulated in the myocardium after AMI. MALAT1 up-regulation plays a critical role in promoting cardiomyocytes apoptosis via targeting miR-144.

Clematichinenoside Attenuates Myocardial Infarction in Ischemia/Reperfusion Injury both In Vivo and In Vitro

Planta Medica ◽  
2013 ◽  
Vol 79 (14) ◽  
pp. 1289-1297 ◽  
Author(s):  
Rui Zhang ◽  
Weirong Fang ◽  
Dan Han ◽  
Lan Sha ◽  
Jie Wei ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion
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