scholarly journals ZYZ-803 Mitigates Endoplasmic Reticulum Stress-Related Necroptosis after Acute Myocardial Infarction through Downregulating the RIP3-CaMKII Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Lingling Chang ◽  
Zhijun Wang ◽  
Fenfen Ma ◽  
Bahieu Tran ◽  
Rui Zhong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Signaling Pathway ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Interacting Protein

Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide, and both cardiac necroptosis and endoplasmic reticulum stress (ERS) have been involved in the pathophysiology of AMI. ZYZ-803 is a hybrid molecule of a dual donor for gasotransmitters H2S and NO. The aim of the present study is to investigate the antinecroptosis role and potential mechanisms of ZYZ-803 in the setting of ERS during AMI injury. In vivo, ZYZ-803 preserves cardiac function and reduces infarct size significantly after 24-hour left coronary artery ligation through revising H2S and NO imbalance. In addition, ZYZ-803 relieves ERS and necroptosis in an AMI heart. In vitro, ZYZ-803 ameliorates ERS-related necroptosis induced by tunicamycin, and such effect has been depending on the receptor-interacting protein 3- (RIP3-) Ca2+-calmodulin-dependent protein kinase (CaMKII) signaling pathway. These findings have identified a novel antinecroptosis potential of ZYZ-803, providing a valuable candidate for cardioprotection in acute myocardial ischemia.

scholarly journals Melatonin Exerts Cardioprotective Effects by Inhibiting NLRP3 Inflammasome-Induced Pyroptosis in Mice following Myocardial Infarction

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Lianghe Wen ◽  
Minnan Wang ◽  
Peiyao Luo ◽  
Xianglin Meng ◽  
Mingyan Zhao
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Cardiac Injury ◽  
Coronary Artery Ligation ◽  
Cardiac Damage ◽  
Artery Ligation ◽  
Cardioprotective Effects

Myocardial infarction- (MI-) induced myocardial damage is mainly attributed to the loss of cardiomyocytes. Pyroptosis is a newly recognized form of programmed cell necrosis that is associated with the progression of MI. Melatonin has been shown to exert cardioprotective effects against cardiac damage in multiple cardiovascular diseases. However, the effect of melatonin on pyroptosis-induced cardiac injury in MI has not been elucidated. Herein, we found that melatonin administration ameliorated cardiac dysfunction and reduced cardiomyocyte death both in mice following coronary artery ligation and in H9C2 cells exposed to hypoxia. The results also showed that pyroptosis was induced both in vivo and in vitro, as evidenced by increased NLRP3, cleaved caspase-1, GSDMD-N, and mature IL-1β and IL-18 levels, and these changes were decreased by melatonin treatment. Furthermore, we observed that TLR4 and NF-κB levels were increased by MI or hypoxia, and these increases were reversed by melatonin. The antipyroptotic action of melatonin was abrogated by treatment with an agonist of the TLR4/NF-κB signaling pathway. Our results indicate that melatonin can exert cardioprotective effects by inhibiting NLRP3 inflammasome-induced pyroptosis through modulation of the TLR4/NF-κB signaling pathway and provide strong evidence for the utility of melatonin in the treatment of MI.

Abstract 365: Targeted Delivery of IGF-1 Following Acute Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Raffay S Khan ◽  
Jay C Sy ◽  
Milton Brown ◽  
Mario D Martinez ◽  
Niren Murthy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Targeted Delivery ◽  
Coronary Artery Ligation ◽  
Nuclear Staining ◽  
Post Injection ◽  
Artery Ligation ◽  
Intact Cells ◽  
Double Stranded Dna

During acute myocardial infarction (MI) there is excessive necrosis of myocardial cells, leading to the release of large amounts of DNA, representing a potential target for drug delivery. Hoechst, a commonly used molecule for staining nuclei, binds to the minor groove of double-stranded DNA and can be functionalized to contain reactive groups such as free amines, sulfhydryls, and biotin moieties. Insulin-like growth factor-1 (IGF-1), a small molecule with a short half-life is protective immediately following MI, though there is potential for long-term toxicity and off-target effects. Therefore, we hypothesized that conjugating IGF-1 to Hoechst would increase targeting of IGF-1 to the injured myocardium. Hoechst-IGF1 (H-IGF1) was synthesized by binding Hoechst-biotin to biotinylated IGF-1 via a fluorescent streptavidin linker. Intact cells did not show nuclear staining with H-IGF1, while permeabilized cells had a significant increase in blue fluorescent Hoechst staining, indicating H-IGF1 was cell impermeable but could still bind DNA. Activity of H-IGF1 was demonstrated by Akt phosphorylation in cultured cardiac progenitor cells and was similar to native IGF-1. To determine in-vivo targeting of H-IGF1 to MI, mice underwent 30 minutes of coronary artery ligation followed by reperfusion (I/R). Six hours following MI, mice were injected intravenously with 70ng of H-IGF1, S-IGF1 (streptavidin bound IGF-1 only) or PBS followed by in vivo imaging at 30 and 120 minutes post-injection. At 30 minutes post-injection, we found 3.2% (2.2 of 70ng) of the injected dose of H-IGF1 in infarcted hearts compared with 1.8% (1.3 of 70ng) of S-IGF1 (n=5-7; p<0.05). To confirm that targeting of H-IGF1 was dependent on binding DNA, H-IGF1 pre-bound to double-stranded DNA was injected intravenously after I/R. This led to a significant (p<0.05) decrease in targeted IGF-1 levels. IGF-1 levels determined by ELISA 2 hours post-injection demonstrated a similar trend with increased targeting of H-IGF1 compared with S-IGF1 treated mice (4.2±0.6 ng vs. 2.4±0.2 ng; p<0.05). In conclusion, our data demonstrate that intravenous delivery of Hoechst-conjugated IGF-1 increases myocardial targeting. This provides a novel strategy for delivery of growth factors for the treatment of MI.

scholarly journals Aucubin Protects against Myocardial Infarction-Induced Cardiac Remodeling via nNOS/NO-Regulated Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Zheng Yang ◽  
Qing-Qing Wu ◽  
Yang Xiao ◽  
Ming Xia Duan ◽  
Chen Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Coronary Artery Ligation ◽  
No Production ◽  
Protective Effects ◽  
Artery Ligation ◽  
Nos Inhibitors

Whether aucubin could protect myocardial infarction- (MI-) induced cardiac remodeling is not clear. In this study, in a mouse model, cardiac remodeling was induced by left anterior descending coronary artery ligation surgery. Mice were intraperitoneally injected with aucubin (10 mg/kg) 3 days post-MI. Two weeks post-MI, mice in the aucubin treatment group showed decreased mortality, decreased infarct size, and improved cardiac function. Aucubin also decreased cardiac remodeling post-MI. Consistently, aucubin protected cardiomyocytes against hypoxic injury in vitro. Mechanistically, we found that aucubin inhibited the ASK1/JNK signaling. These effects were abolished by the JNK activator. Moreover, we found that the oxidative stress was attenuated in both in vivo aucubin-treated mice heart and in vitro-treated cardiomyocytes, which caused decreased thioredoxin (Trx) consumption, leading to ASK1 forming the inactive complex with Trx. Aucubin increased nNOS-derived NO production in vivo and vitro. The protective effects of aucubin were reversed by the NOS inhibitors L-NAME and L-VINO in vitro. Furthermore, nNOS knockout mice also reversed the protective effects of aucubin on cardiac remodeling. Taken together, aucubin protects against cardiac remodeling post-MI through activation of the nNOS/NO pathway, which subsequently attenuates the ROS production, increases Trx preservation, and leads to inhibition of the ASK1/JNK pathway.

scholarly journals Exosomal miR-218-5p/miR-363-3p from Endothelial Progenitor Cells Ameliorate Myocardial Infarction by Targeting the p53/JMY Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Xiao Ke ◽  
Rongfeng Yang ◽  
Fang Wu ◽  
Xing Wang ◽  
Jiawen Liang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathway ◽  
Myocardial Fibrosis ◽  
Regulatory Protein ◽  
Luciferase Reporter ◽  
Coronary Artery Ligation ◽  
Endothelial Progenitor ◽  
Artery Ligation ◽  
Qrt Pcr

Accumulating evidence has shown that endothelial progenitor cell-derived exosomes (EPC-Exos) can ameliorate myocardial fibrosis. The purpose of the present study was to investigate the effects of EPC-Exos-derived microRNAs (miRNAs) on myocardial infarction (MI). A miRNA-Seq dataset of miRNAs differentially expressed between EPCs and exosomes was collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the miRNA expression indicated by miRNA-Seq. Immunofluorescence, cell proliferation, and angiogenesis assays were employed to investigate the effects of miRNAs on cardiac fibroblasts (CFs) in vitro. Interactions between miRNAs and their respective targets were examined via immunoblotting, qRT-PCR, and luciferase reporter assays. An MI rat model was constructed, and various staining and immunohistochemical assays were performed to explore the mechanisms underlying the miRNA-mediated effects on MI. miR-363-3p and miR-218-5p were enriched in EPC-Exos, and miR-218-5p and miR-363-3p mimic or inhibitor enhanced or suppressed CF proliferation and angiogenesis, respectively. miR-218-5p and miR-363-3p regulated p53 and junction-mediating and regulatory protein (JMY) by binding to the promoter region of p53 and the 3 ′ untranslated region of JMY. Additionally, treatment of CFs with Exo-miR-218-5p or Exo-miR-363-3p upregulated p53 and downregulated JMY expression, promoted mesenchymal-endothelial transition, and inhibited myocardial fibrosis. Administration of exosomes containing miR-218-5p mimic or miR-363-3p mimic ameliorated left coronary artery ligation-induced MI and restored myocardial tissue integrity in the MI model rats. In summary, these results show that the protective ability of EPC-Exos against MI was mediated by the shuttled miR-218-5p or miR-363-3p via targeting of the p53/JMY signaling pathway.

iASPP protects the heart from ischemia injury by inhibiting p53 expression and cardiomyocyte apoptosis

2020 ◽  
Author(s):  
Timur Yagudin ◽  
Yue Zhao ◽  
Haiyu Gao ◽  
Yang Zhang ◽  
Ying Yang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Cardiomyocyte Apoptosis ◽  
Coronary Artery Ligation ◽  
Novel Therapy ◽  
Artery Ligation ◽  
P53 Expression

Abstract Currently, there remains a great need to elucidate the molecular mechanism of acute myocardial infarction in order to facilitate the development of novel therapy. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is a member of the ASPP family proteins and an evolutionarily preserved inhibitor of p53 that is involved in many cellular processes, including apoptosis of cancer cells. The purpose of this study was to investigate the possible role of iASPP in acute myocardial infarction. The protein level of iASPP was markedly reduced in the ischemic hearts in vivo and hydrogen peroxide-exposed cardiomyocytes in vitro. Overexpression of iASPP reduced the infarct size and cardiomyocyte apoptosis of mice subjected to 24 h of coronary artery ligation. Echocardiography showed that cardiac function was improved as indicated by the increase in ejection fraction and fractional shortening. In contrast, knockdown of iASPP exacerbated cardiac injury as manifested by impaired cardiac function, increased infarct size, and apoptosis rate. Mechanistically, overexpression of iASPP inhibited, while knockdown of iASPP increased the expressions of p53 and Bax, the key regulators of apoptosis. Taken together, our results suggested that iASPP is an important regulator of cardiomyocyte apoptosis, which represents a potential target in the therapy of myocardial infarction.

scholarly journals Exosomal miR-218-5p/miR-363-3p from Endothelial Progenitor Cells Ameliorate Myocardial Infarction by Targeting the P53/JMY Signaling Pathway

2021 ◽  
Author(s):  
Xiao Ke ◽  
Rongfeng Yang ◽  
Fang Wu ◽  
Xing Wang ◽  
Jiawen Liang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathway ◽  
Myocardial Fibrosis ◽  
Regulatory Protein ◽  
Luciferase Reporter ◽  
Coronary Artery Ligation ◽  
Endothelial Progenitor ◽  
Artery Ligation ◽  
Qrt Pcr

Abstract BackgroundAccumulating evidence has shown that endothelial progenitor cell-derived exosomes (EPC-Exos) can ameliorate myocardial fibrosis. The purpose of the present study was to investigate the effects of EPC-Exos-derived microRNAs (miRNAs) on myocardial infarction (MI). MethodsA miRNA-Seq dataset of miRNAs differentially expressed between EPCs and exosomes was collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the miRNA expression indicated by miRNA-Seq. Immunofluorescence, cell proliferation and angiogenesis assays were employed to investigate the effects of miRNAs on cardiac fibroblasts (CFs) in vitro. Interactions between miRNAs and their respective targets were examined via immunoblotting, qRT-PCR and luciferase reporter assays. An MI rat model was constructed, and various staining and immunohistochemical assays were performed to explore the mechanisms underlying the miRNA-mediated effects on MI. ResultsmiR-363-3p and miR-218-5p were enriched in EPC-Exos, and miR-218-5p and miR-363-3p mimic or inhibitor enhanced or suppressed CF proliferation and angiogenesis, respectively. miR-218-5p and miR-363-3p regulated P53 and junction-mediating and regulatory protein (JMY) by binding to the promoter region of P53 and the 3’ untranslated region of JMY. Additionally, treatment of CFs with exo-miR-218-5p or miR-363-3p mimic upregulated P53 and down-regulated JMY expression, promoted mesenchymal-endothelial transition and inhibited myocardial fibrosis. Administration of exosomes containing miR-218-5p mimic or miR-363-3p mimic ameliorated left coronary artery ligation-induced MI and restored myocardial tissue integrity in the MI model rats. ConclusionsIn summary, these results show that the protective ability of EPC-Exos against MI was mediated by the shuttled miR-218-5p or miR-363-3p via targeting of the P53/JMY signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document