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.

Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Benjamin Vogel ◽  
Hisahito Shinagawa ◽  
Ullrich Hofmann ◽  
Georg Ertl ◽  
Stefan Frantz
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Artery Ligation ◽  
High Concentrations

Rationale: Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones. Objective: We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity. Methods and Results: After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm 2 ]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p<0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p<0.05; n=7 vs 8). Conclusions: Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.

scholarly journals Protective Effects of Rhodiola Crenulata Extract on Hypoxia-Induced Endothelial Damage via Regulation of AMPK and ERK Pathways

2018 ◽  
Vol 19 (8) ◽  
pp. 2286 ◽  
Author(s):  
Pi-Kai Chang ◽  
I-Chuan Yen ◽  
Wei-Cheng Tsai ◽  
Tsu-Chung Chang ◽  
Shih-Yu Lee
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Umbilical Vein ◽  
Hypoxic Exposure ◽  
No Production ◽  
Root Extract ◽  
Protective Effects ◽  
Rhodiola Crenulata

Rhodiola crenulata root extract (RCE) has been shown to possess protective activities against hypoxia both in vitro and in vivo. However, the effects of RCE on response to hypoxia in the endothelium remain unclear. In this study, we aimed to examine the effects of RCE in endothelial cells challenged with hypoxic exposure and to elucidate the underlying mechanisms. Human umbilical vein endothelial cells were pretreated with or without RCE and then exposed to hypoxia (1% O2) for 24 h. Cell viability, nitric oxide (NO) production, oxidative stress markers, as well as mechanistic readouts were studied. We found that hypoxia-induced cell death, impaired NO production, and oxidative stress. These responses were significantly attenuated by RCE treatment and were associated with the activation of AMP-activated kinase and extracellular signal-regulated kinase 1/2 signaling pathways. In summary, we showed that RCE protected endothelial cells from hypoxic insult and suggested that R. crenulata might be useful for the prevention of hypoxia-associated vascular dysfunction.

scholarly journals Protective effects of Salidroside on cardiac function in mice with myocardial infarction

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pengsheng Chen ◽  
Jia Liu ◽  
Hongyun Ruan ◽  
Miaomiao Zhang ◽  
Peng Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Normal Saline ◽  
Myocardial Inflammation ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Myocardial Remodeling ◽  
Artery Ligation ◽  
Post Surgery

AbstractSalidroside (SAL) is the major ingredient of Rhodiola rosea, and has been traditionally used in Chinese medicine for decades. Numerous studies have demonstrated the protective effects of SAL for myocardial ischemia. However, it is yet to be deciphered whether SAL has cardioprotective effects after myocardial infarction (MI) in vivo. In the present study, we established a mouse MI model via coronary artery ligation. The aim was to investigate whether SAL treatment could reduce mortality, improve cardiac function and attenuate myocardial remodeling in MI mice. Post-surgery, mice were randomly administered SAL or normal saline. After 21 days, SAL was found to significantly reduce mortality, improve cardiac function, reduce fibrosis and infarct size compared to normal saline. In addition, oral administration of SAL could attenuate myocardial inflammation and apoptosis and promote angiogenesis. SAL down-regulated the expression levels of TNF-α, TGF-β1, IL-1β, Bax and up-regulate the expression of Bcl-2, VEGF, Akt and eNOS. These results indicated that SAL could alleviate the pathological processes of myocardial remodeling in MI mice, and may be a potentially effective therapeutic approach for the management of clinical ischemic cardiovascular diseases.

scholarly journals ATP-binding cassette transporter Abcg2 lineage contributes to the cardiac vasculature after oxidative stress

2014 ◽  
Vol 306 (12) ◽  
pp. H1610-H1618 ◽  
Author(s):  
Travis J. Maher ◽  
Yi Ren ◽  
Qinglu Li ◽  
Elizabeth Braunlin ◽  
Mary G. Garry ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immunohistochemical Analysis ◽  
Atp Binding ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Systemic Oxidative Stress ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

Due to their specialized location, stem and progenitor cells are often exposed to oxidative stress. Although ATP-binding cassette transporter subfamily G member 2 (Abcg2)-expressing cells have been implicated in cardiac protective mechanisms involving oxidative stress, there remains a lack of understanding regarding the behavior of cardiac Abcg2-expressing cells when exposed to ROS. The aim of the present study was to characterize the response of the cardiac Abcg2 lineage to oxidative stress. In vitro analysis demonstrated that the antioxidant program regulated by Abcg2 is dependent on a functional transporter. Delivery of paraquat dichloride (PQ), a systemic oxidative stress-inducing agent, to mice confirmed that Abcg2 provides a survival benefit. When exposed to PQ, reporter mice showed an increase in the Abcg2 lineage. Transcriptional and immunohistochemical analysis of Abcg2 lineage-positive cells revealed an enhanced vascular commitment after stress. Finally, preconditioning with PQ demonstrated a reduction in scar size and an increase in angiogenesis after permanent left coronary artery ligation. In conclusion, the data suggest that Abcg2 plays a cytoprotective role in response to in vivo oxidative stress. The contribution of the Abcg2 lineage to the vasculature in the heart is increased after PQ delivery.

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.

miR-187 modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2

2021 ◽  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Protective Effect ◽  
Myocardial Infarct ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Ros Generation ◽  
Downstream Target

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.

scholarly journals Hexarelin exerts neuroprotective and antioxidant effects against hydrogen peroxide-induced toxicity through the modulation of MAPK and PI3K/Akt patways in Neuro-2A cells

2020 ◽  
Author(s):  
Ramona Meanti ◽  
Laura Rizzi ◽  
Elena Bresciani ◽  
Laura Molteni ◽  
Vittorio Locatelli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Apoptotic Cell ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cell Line ◽  
Inhibitory Influence ◽  
No Production ◽  
Mrna Levels

AbstractHexarelin, a synthetic hexapeptide, protects cardiac and skeletal muscles by inhibiting apoptosis, both in vitro and in vivo. Moreover, evidence suggests that hexarelin could have important neuroprotective bioactivity.Oxidative stress and the generation of free radicals has been implicated in the etiologies of several neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and multiple sclerosis. In addition to direct oxidative stress, exogenous hydrogen peroxide (H2O2) can penetrate biological membranes and enhance the formation of other reactive oxygen species.The aim of this study was to examine the inhibitory influence of hexarelin on H2O2-induced apoptosis in Neuro-2A cells, a mouse neuroblastoma cell line. Our results indicate that H2O2 reduced the viability of Neuro-2A cells in a dose-related fashion. Furthermore, H2O2 induced significant changes in the morphology of Neuro-2A cells, reflected in the formation of apoptotic cell bodies, and an increase of nitric oxide (NO) production. Hexarelin effectively antagonized H2O2 oxidative damage to Neuro-2A cells as indicated by improved cell viability, normal morphology and reduced nitrite (NO2−) release. Hexarelin treatment of Neuro-2A cells also reduced mRNA levels of caspases−3 and −7 and those of the pro-apoptotic molecule Bax; by contrast, hexarelin treatment increased anti-apoptotic Bcl-2 mRNA levels. Hexarelin also reduced MAPKs phosphorylation induced by H2O2 and concurrently increased p-Akt protein expression.In conclusion, our results identify several neuroprotective and anti-apoptotic effects of hexarelin. These properties suggest that further investigation of hexarelin as a neuroprotective agent in an investigational and therapeutic context are merited.

Abstract 12648: Deletion of 12/15 Lipoxygenase Improves Left Ventricle Function and Survival by Resolving Inflammation Post Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vasundhara Kain ◽  
Kevin A Ingle ◽  
Janusz Kabarowski ◽  
Sumanth D Prabhu ◽  
Ganesh V Halade
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Survival Rates ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Lv Remodeling ◽  
Early Expression ◽  
Cox 2

12/15 lipoxygenase (LOX) is crucial in the inflammatory process leading to diabetes and atherosclerosis. However, the role of 12/15 LOX in myocardial infarction (MI) and left ventricle (LV) remodeling is unclear. We assessed the role of 12/15 LOX in resolving inflammation in post-MI LV remodeling. 8-12 weeks old C57BL/6J wild-type (WT; n=67) and 12/15 LOX (LOX –/– ; n=78) male mice were subjected to permanent coronary artery ligation surgery and monitored through day (d)1 and d5. No MI surgery mice were maintained as d0 naïve controls. LOX -/- mice showed higher survival rate, improved fractional shortening with reduced remodeling and edema index than WT at d1 and d5 post-MI (all p<0.05). LOX -/- mice showed increased Cxcl5 expression at d1 post-MI, consistent with stimulated neutrophil recruitment in the infarct region that was decreased at d5 compared to WT. LOX -/- mice infarct had increased expression of Ccl2 and Cxcl1, that stimulated an earlier recruitment of monocytes with increased macrophages population at d5 (all p<0.05) compared to WT. The altered kinetics of immune cells post-MI indicates a rapid resolving phase, through increase in alternative macrophage phenotypes with reduced collagen density in LOX -/- mice compared to WT mice at d5 post-MI. LOX -/- mice showed a coordinated COX-1 and COX-2 response at d1 post MI, leading to an evident increase in 5-LOX and hemoxygenase-1 (HO-1) at d5 post-MI. 12/15 LOX deletion enhanced the recruitment of alternative macrophages with secretion of HO-1 to resolve inflammation. In-vitro addition of LOX metabolite 12 hydroxyeicosatetraenoic acid to LOX -/- fibroblast induced early expression of COX-2 and 5-LOX compared to WT, indicating 5LOX role in resolution of inflammation. Post-MI increased expression of TIMP-1 and decrease in MMP-9 at d1 and α-SMA at d5 in LOX -/- mice suggested controlled differentiation of fibroblast-to-myofibroblast which is key event during ventricular tissue repair and resolving phase. This change is supported by increased expression of tgf-βi, ctgf and admats-2 (all P<0.05) at d5 post MI. In conclusion, absence of 12/15 LOX improves post-MI survival rates and attenuates LV dysfunction by resolving inflammation through coordination of 5-LOX and HO-1 as key inflammation resolving enzymes.

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