Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction

2016 ◽  
Vol 310 (1) ◽  
pp. H20-H28 ◽  
Author(s):  
Mari Mayorga ◽  
Matthew Kiedrowski ◽  
Patricia Shamhart ◽  
Farhad Forudi ◽  
Kristal Weber ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Hypoxia Inducible Factor ◽  
Cardiac Repair ◽  
Cxcr4 Expression ◽  
Border Zone ◽  
H9c2 Cells ◽  
Myocardial Repair ◽  
Infarct Zone ◽  
Cxcr4 Axis

The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.

scholarly journals Ultrasound-Targeted Microbubble Destruction Improves the Migration and Homing of Mesenchymal Stem Cells after Myocardial Infarction by Upregulating SDF-1/CXCR4: A Pilot Study

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Lu Li ◽  
Shengzheng Wu ◽  
Zheng Liu ◽  
Zhongxiong Zhuo ◽  
Kaibin Tan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cxcr4 Expression ◽  
Ischemic Myocardium ◽  
Potential Mechanism ◽  
Cxcr4 Axis

Mesenchymal stem cell (MSC) therapy shows considerable promise for the treatment of myocardial infarction (MI). However, the inefficient migration and homing of MSCs after systemic infusion have limited their therapeutic applications. Ultrasound-targeted microbubble destruction (UTMD) has proven to be promising to improve the homing of MSCs to the ischemic myocardium, but the concrete mechanism remains unclear. We hypothesize that UTMD promotes MSC homing by upregulating SDF-1/CXCR4, and this study was aimed at exploring this potential mechanism. We analyzed SDF-1/CXCR4 expression after UTMD treatment in vitro and in vivo and counted the number of homing MSCs in MI areas. The in vitro results demonstrated that UTMD not only led to elevated secretion of SDF-1 but also resulted in an increased proportion of MSCs that expressed surface CXCR4. The in vivo findings show an increase in the number of homing MSCs and higher expression of SDF-1/CXCR4 in the UTMD combined with MSCs infusion group compared to other groups. In conclusion, UTMD can increase SDF-1 expression in the ischemic myocardium and upregulate the expression of surface CXCR4 on MSCs, which provides a molecular mechanism for the homing of MSCs assisted by UTMD via SDF-1/CXCR4 axis.

Abstract 14474: Cdk9-activated Sgk3 Promotes Myocardial Repair and Regeneration After Myocardial Infarction via Gsk-3Å/Å-catenin Pathway

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
YaFei Li ◽  
Tianwen Wei ◽  
Fan Yi ◽  
Hao Wang ◽  
Liansheng Wang
Keyword(s):  
Myocardial Infarction ◽  
Time Window ◽  
Cardiac Regeneration ◽  
Cardiac Repair ◽  
Border Zone ◽  
Regeneration Ability ◽  
Loss Of Function ◽  
Myocardial Repair ◽  
Quantitative Phosphoproteomics

Background: Neonatal heart maintains entire regeneration capacity in a transient regeneration window, but the adult heart loses this function. This process involves numberous core hubs dysregulation of expression and activity that adversely affect the myocardium regeneration ability. Present study screened a functional kinase of serine/threonine-protein kinase 3 (SGK3) in cardiac regeneration after neonatal myocardial infarction (MI) using quantitative phosphoproteomics. Methods: We used quantitative phosphoproteomics data of infarct border zone in newborn heart after MI to identify regeneration related kinases. Gain- and loss-of-function experiments were performed to determine the effect of SGK3 in cardiomyocyte (CM) proliferation and cardiac repair after apical resection (AR) or MI. Pull-down assay and co-immunoprecipitation (Co-IP) experiments were conducted to investigate the direct binding target proteins of SGK3. Results: SGK3 protein expression was highly expressed at postnatal day 1 (P1), reduced at postnatal day 7 (P7) until adult. In vitro, CM proliferation ratio was elevated by SGK3 overexpression, while it was decreased by knockdown of SGK3. In vivo, inhibition of SGK3 shortened the time window of cardiac regeneration after AR in neonatal mice, and overexpression of SGK3 significantly promoted CM proliferation and cardiac repair after MI. Mechanistically, SGK3 could be directly combined with and activated by cyclindependent kinase 9 (CDK9). Inhibition of CDK9 partially abolished the effect of SGK3 on CM proliferation. Moreover, SGK3 could repress GSK-3β activity and increase β-catenin expression. Conclusions: Our study revealed a key role of SGK3 in cardiac regeneration following AR or MI injury, which may reopen a novel therapeutic avenue for MI.

scholarly journals Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

2020 ◽  
Vol 21 (9) ◽  
pp. 3359
Author(s):  
Zoltán Giricz ◽  
András Makkos ◽  
Rolf Schreckenberg ◽  
Jochen Pöling ◽  
Holger Lörchner ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Common Mechanism ◽  
Structural Adaptation ◽  
Infarct Zone ◽  
Rat Cardiomyocytes ◽  
Ischemic Conditioning

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species.

scholarly journals Influence of Cell Treatment with PDGF-BB and Reperfusion on Cardiac Persistence of Mononuclear and Mesenchymal Bone Marrow Cells after Transplantation into Acute Myocardial Infarction in Rats

2009 ◽  
Vol 18 (8) ◽  
pp. 847-853 ◽  
Author(s):  
Benjamin Krausgrill ◽  
Marius Vantler ◽  
Volker Burst ◽  
Martin Raths ◽  
Marcel Halbach ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Cell Loss ◽  
Border Zone ◽  
High Dose ◽  
Myocardial Repair ◽  
Intramyocardial Injection ◽  
Rat Hearts ◽  
Marrow Cells

Bone marrow cells are used for cell therapy after myocardial infarction (MI) with promising results. However, cardiac persistence of transplanted cells is rather low. Here, we investigated strategies to increase the survival and cardiac persistence of mononuclear (MNC) and mesenchymal (MSC) bone marrow cells transplanted into infarcted rat hearts. MNC and MSC (male Fischer 344 rats) were treated with different doses of PDGF-BB prior to intramyocardial injection into border zone of MI (syngeneic females, permanent LAD ligation) and hearts were harvested after 5 days and 3 weeks. In additional experiments, untreated MNC and MSC were injected immediately after permanent or temporary LAD ligation and hearts were harvested after 48 h, 5 days, 3 weeks, and 6 weeks. DNA of the hearts was isolated and the number of donor cells was determined by quantitative real-time PCR with Y chromosome-specific primers. There was a remarkable though not statistically significant ( p = 0.08) cell loss of ~46% between 5 days and 3 weeks in the control group, which was completely inhibited by treatment with high dose of PDGF-BB. Forty-eight hours after reperfusion only 10% of injected MSC or 1% for MNC were found in the heart, decreasing to 1% for MSC and 0.5% for MNC after 6 weeks. These numbers were lower than after permanent LAD ligation for both MNC and MSC at all time points studied. Treatment with PDGF-BB seems to prevent loss of transplanted bone marrow cells at later times presumably by inhibition of apoptosis, while reperfusion of the occluded artery enhances cell loss at early times putatively due to enhanced early wash-out. Further investigations are needed to substantially improve the persistence and survival of grafted bone marrow cells in infarcted rat hearts, in order to fully explore the therapeutic potential of this novel treatment modality for myocardial repair.

scholarly journals Ezh2 as an epigenetic checkpoint regulator during monocyte differentiation: a potential target to improve cardiac repair after myocardial infarction

2021 ◽  
Author(s):  
Julie Rondeaux ◽  
Deborah Groussard ◽  
Sylvanie Renet ◽  
Virginie Tardif ◽  
Anaïs Dumesnil ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Macrophage Polarization ◽  
Human Monocyte ◽  
Cardiac Repair ◽  
Monocyte Differentiation ◽  
Cardiac Inflammation ◽  
H3k27 Methylation ◽  
Epigenetic Modulation

Abstract Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative M2-like macrophage polarization, essential for cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first-time an EZH2 ectopic, and putative inactive, cytoplasmic localization of the epigenetic enzyme, during monocyte differentiation in vitro as well as in M2 macrophages in vivo during post-MI cardiac inflammation. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation at the promoter of bivalent genes, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction after MI in vivo. In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.

scholarly journals Exosomes derived from human umbilical cord MSCs rejuvenate aged MSCs and enhance their functions for myocardial repair

2020 ◽  
Author(s):  
Ning Zhang ◽  
JinYun Zhu ◽  
QunChao Ma ◽  
Yun Zhao ◽  
YingChao Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Umbilical Cord ◽  
Cardiac Repair ◽  
Human Umbilical Cord ◽  
Bone Marrow Mscs ◽  
Myocardial Repair ◽  
Related Factors

Abstract Background: Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair. Methods: Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCsExo. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardiac infarction(MI). Results: We found the activity of senescence-associated β-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, anti-apoptotic and paracrine effect were increased in OMSCsExo. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCsExo as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCsExo than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3’UTR. Conclusion: Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1.

Abstract 217: Long Non-coding RNA Myocardial Infarction-associated Transcript (MIAT) Protects Cardiac Progenitor Cells From Oxidative Stress-induced Cell Death

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Liu Yang ◽  
Yang Yu ◽  
Baron Arnone ◽  
Chan Boriboun ◽  
Jiawei Shi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cell Death ◽  
Progenitor Cells ◽  
Cardiac Cells ◽  
Border Zone ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells

Background: Long non-coding RNAs (lncRNAs) are an emerging class of RNAs with no or limited protein-coding capacity; a few of which have recently been shown to regulate critical biological processes. Myocardial infarction-associated transcript (MIAT) is a conserved mammalian lncRNA, and single nucleotide polymorphisms (SNPs) in 6 loci of this gene have been identified to be strongly associated with the incidence and severity of human myocardial infarction (MI). However, whether and how MIAT impacts on the pathogenesis of MI is unknown. Methods & Results: Quantitative RT-PCR analyses revealed that MIAT is expressed in neonatal mouse heart and to a lesser extent in adult heart. After surgical induction of MI in adult mice, MIAT starts to increase in 2 hours, peaks at 6 hours in atria and 12 hours in ventricles, and decreases to baseline at 24 hours. Fluorescent in situ hybridization (FISH) revealed a slight increase in the number of MIAT-expressing cells in the infarct border zone at 12 hours post-MI. Moreover, qRT-PCR analyses of isolated cardiac cells revealed that MIAT is predominantly expressed in cardiosphere-derived cardiac progenitor cells (CPCs). Treatment of CPCs with H 2 O 2 led to a marked upregulation of MIAT, while knockdown (KD) of MIAT resulted in a significantly impaired cell survival in vitro with H 2 O 2 treatment and in vivo after administered in the ischemic/reperfused heart. Notably, bioinformatics prediction and RNA immunoprecipitation identified FUS (fused in sarcoma) as a novel MIAT-interacting protein. FUS-KD CPCs displayed reduced cell viability and increased apoptosis under oxidative stress. Furthermore, MIAT overexpression enhanced survival of WT CPCs but not FUS-KD CPCs, suggesting that the protective role of MIAT is mediated by FUS. Conclusions: MIAT interacts with FUS to protect CPCs from oxidative stress-induced cell death.

Abstract 12105: Targeted Delivery of Therapeutic Agents After Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Siva Sai Krishna Dasa ◽  
Marc E Seamen ◽  
Brent A French ◽  
Kimberly A Kelly
Keyword(s):  
Myocardial Infarction ◽  
Phage Display ◽  
Targeted Delivery ◽  
Cell Types ◽  
Phage Display Library ◽  
Border Zone ◽  
Cell Type ◽  
Cellular Targets ◽  
Cell Type Specific

Introduction: Current therapies for heart failure (HF) after myocardial infarction (MI) only slow the progression of LV remodeling and have little capacity to regenerate cardiac muscle lost to MI. To expedite targeted delivery of regenerative therapies post-MI, we hypothesized that suitable targets could be identified by biopanning the heart with a phage display library in a mouse model of MI. Methods: A phage display library was biopanned in vivo to identify peptides specific for the infarct/border zone 4 days post-MI. Fluorescence molecular tomography (FMT) followed by tissue immunofluorescence was performed to interrogate the specificity of phage groups and individual clones with targeted phage at VT680 and neg control phage at VT750. The VT680 fluorophore on the targeted phage clones was then used to identify the cellular targets of those clones by counter-staining with antibodies against cell types of interest. Results: We identified phage clones specific for endothelium, cardiomyocytes, inflammatory fibroblasts and c-Kit+ cells present in the border zone post-MI. Liposomes conjugated with different cell type specific peptides had different accumulation rates in the post-infarct heart as visualized by FMT imaging (Fig. 1a). Immunofluorescence analysis demonstrated cell-type specific association of the targeted liposomes with cells expressing c-Kit, CD31 and Hrnr (Figs. 1b&c). We have also been successful in remote loading of anti-apoptotic and immune suppresive drugs into these liposomes and are currently studying their effect in mice after MI. Conclusions: Peptides identified by this screen enable the targeting of different cell types present in the border zone with different drugs. Identifying the molecular binding partners for these peptides may yield insight into the various events/pathways that evolve after a myocardial infarction.

Abstract 17202: Synthetic Modified RNA Driven Delivery of Insulin-Like Growth Factor-1 Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Chien-Ling Huang ◽  
Anne-Laure Leblond ◽  
Elizebeth C Turner ◽  
Arun H Kumar ◽  
Donnchadh M O’Sullivan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Border Zone ◽  
Insulin Like Growth Factor ◽  
Area At Risk ◽  
Akt Phosphorylation ◽  
Post Transfection ◽  
Erk Phosphorylation ◽  
Induced Apoptosis

To extend the temporal window for cytoprotection in cardiomyocytes undergoing apoptosis after hypoxia and myocardial infarction (MI), a synthetic modified RNA (modRNA) was used to drive delivery of insulin-like growth factor-1 (IGF1) within the area at risk in a murine model of MI. Transient transfection of synthetic GFP modRNA as an tracking indicator, with polyethylenimine (PEI)-based nanoparticle, showed efficient delivery of modRNA derived protein and minimum cytotoxicity in HL-1 cardiomyocytes (CM; 44±5%). ModRNA-IGF1 protein expression and secreted levels increased 3.5 fold ( p <0.05) at 24 hours and peaked at 48 hours post-transfection. The expression efficiency of modRNA was further enhanced (~2 fold at 24 hours post-transfection; p <0.05) under hypoxia-induced apoptosis conditions. ModRNA augmented secreted and cell associated IGF1 promoting CM survival and abrogating cell apoptosis (71±5% in controls to 37±7%, p <0.05). Translation of modRNA-IGF1 was sufficient to induce downstream increases in Akt and Erk phosphorylation (3 fold and 2 fold, respectively; p <0.01). Downregulation of IGF1 specific miRNA-1 and -133 (52% and 56%, respectively; p <0.01) but not miR-145 expression, was also confirmed. As proof of concept, intramyocardial delivery of modRNA-IGF1 but not control modRNA-GFP significantly decreased in TUNEL-positive cells within the infarct border zone (BZ) at 24 hours (22±3% versus 53±8% in controls, p <0.01). Akt phosphorylation was augmented while caspase-9 activity and cleavage was downregulated in the infarct BZ compared to controls ( p <0.05). These findings demonstrate extended in vivo cytoprotective effect of IGF1 24 hours post-MI driven by synthetic modRNA delivery. This provides a novel strategy to reduce ischemic injury by controlled release of IGF1 using a controllable bioactive nanoparticle for ‘short burst’ IGF1 cytoprotective therapy.

Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation

2007 ◽  
Vol 293 (3) ◽  
pp. H1772-H1780 ◽  
Author(s):  
Julia Feygin ◽  
Abdul Mansoor ◽  
Peter Eckman ◽  
Cory Swingen ◽  
Jianyi Zhang
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Stem Cell Transplantation ◽  
Wall Stress ◽  
Border Zone ◽  
Infarct Zone ◽  
Beneficial Effects ◽  
Myocardial Contractile ◽  
Contractile Performance

Preclinical and clinical studies have demonstrated that stem cell transplantation can improve the left ventricular (LV) contractile performance, yet the underlying mechanisms remain unknown. We examined whether mesenchymal stem cell (MSC) transplantation-induced beneficial effects are secondary to paracrine-associated improvements in LV contractile performance, wall stress, and myocardial bioenergetics in hearts with postinfarction LV remodeling. Myocardial contractile function and bioenergetics were compared 4 wk after acute myocardial infarction in normal pigs ( n = 6), untreated pigs with myocardial infarction (MI group; n = 6), and pigs receiving autologous MSC transplantation (MI + MSC group; n = 5). A distal occlusion of the left anterior descending coronary artery instigated significant myocardial hypertrophy. Ejection fraction decreased from 55.3 ± 3.1% (normal) to 30.4 ± 2.3% (MI group; P < 0.01) and to 45.4 ± 3.1% (MI + MSC group; P < 0.01 vs. MI). Hearts in the MI group developed severe contractile dyskinesis in the infarct zone and border zone (BZ). MSC transplantation significantly improved contractile performance from dyskinesis to active contraction ( P < 0.01 vs. MI). BZ systolic wall stress was severely increased in MI hearts but significantly improved after MSC transplantation ( P < 0.01 vs. MI). The BZ demonstrated profound bioenergetic abnormalities in MI pigs; this was significantly improved after MSC transplantation ( P < 0.01 vs. MI). Patchy spared myocytes were found in the infarct zone of hearts receiving MSC transplantation but not in control hearts. These data demonstrate that MSC transplantation into the BZ causes significant improvements in myocardial contractile performance and reduction in wall stress, which ultimately results in significant bioenergetic improvements. Low cell engraftment indicates that MSCs did not provide a structural contribution to the damaged heart and that the observed beneficial effects likely resulted from paracrine repair mechanisms.

Sign in / Sign up

Export Citation Format

Share Document