The Wnt Inhibitor sFRP2 Enhances Mesenchymal Stem Cell Engraftment, Granulation Tissue Formation and Myocardial Repair

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1365-1365
Author(s):  
Maria Paula Alfaro ◽  
Matthew Pagni ◽  
Alicia Vincent ◽  
Michael F. Hill ◽  
Ethan Lee ◽  
...  
Keyword(s):  
Infarct Size ◽  
Granulation Tissue ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Human Mscs ◽  
Myocardial Repair ◽  
Acute Myocardial Infarct ◽  
Intramyocardial Injection

Abstract Cell-based therapies using bone marrow-derived mesenchymal stem cells (MSCs) for organ regeneration are being pursued for cardiac disease, orthopedic injuries and biomaterial fabrication. The molecular pathways that regulate MSC-mediated regeneration or enhance their therapeutic efficacy are, however, poorly understood. In an attempt to elucidate a way to strengthen the regenerative potential of MSCs, preliminary studies in our lab were performed comparing MSCs isolated from wildtype and regenerative mouse strains. The MRL/MpJ mouse has been described as a “super healer” mouse that is able to repair soft tissue with minimal scaring. MSCs were isolated from the MRL/MpJ mouse (MRL-MSCs) and from C57/Bl6 mice (WT-MSCs) and their differing qualities assessed. Compared to WT-MSCs, MRL-MSCs demonstrated increased proliferation in vitro. We utilized a Poly-vinyl alcohol (PVA) sponge model of repair stimulation to assess their capacity to generate wound repair tissue. We observed that the MRL-MSCs demonstrated increased in vivo engraftment, experimental granulation tissue reconstitution, and tissue vascularity. The MRL-MSCs also reduced infarct size and improved cardiac function as compared to WT-MSCs in a murine acute myocardial infarct model. Genomic and functional analyses indicated a downregulation of the canonical Wnt pathway in MRL-MSCs characterized specifically by upregulation of secreted frizzled related proteins (sFRPs). In vitro proliferation studies confirmed that recombinant sFRP2 mediated enhanced proliferation of both mouse and human MSCs. Based on these observations, we hypothesized that sFRP2 served an important role in MSC-mediated repair and regeneration. We generated WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction to test this hypothesis. sFRP2-MSCs maintained their ability for multilineage differentiation in vitro and proliferated faster than the vector only control MSCs (GFP-MSCs). When implanted in vivo in the PVA sponge model, the sFRP2-MSCs recapitulated the MRL phenotype by mediating greater, more vascularized granulation tissue. Moreover, periinfarct intramyocardial injection of sFRP2-MSCs resulted in reduced infarct size, favorable remodeling and better preserved left ventricular function following acute myocardial infarct in mice. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype of MSCs.

Abstract 13306: Impella Combined With Extracorporeal Membrane Oxygenation Synergistically Unloads the Left Ventricle and Reduces Infarct Size in a Model of Myocardial Infarction With Cardiogenic Shock

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Genya Sunagawa ◽  
Keita Saku ◽  
Takuya Nishikawa ◽  
Nobuhiro Suematsu ◽  
Toru Kubota ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Cardiogenic Shock ◽  
Infarct Size ◽  
Coronary Arteries ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Assist Device ◽  
Acute Myocardial Infarct ◽  
Membrane Oxygenation ◽  
Coronary Ligation

Introduction: Extracorporeal membrane oxygenation (ECMO) supports hemodynamics in cardiogenic shock (CS) at the expense of left ventricular (LV) overload. LV assist device (LVAD) also supports hemodynamics, whereas LVAD unloads LV. Therefore, the combination of ECMO and LVAD would augment hemodynamic support and unload LV. We hypothesized that the combination therapy in acute myocardial infarct (AMI) in CS could synergistically improve hemodynamics and unload LV, which, in turn, reduces infarct size. Methods: In protocol 1, we ligated coronary arteries and created AMI with CS in 5 mongrel dogs (15.1±0.3 kg). We transvascularly introduced Impella CP into LV. We kept the ECMO flow constant at 1.8L/min. We compared hemodynamics and the LV pressure-volume area (PVA, an index of LV oxygen consumption) under 3 conditions; Control, ECMO, and ECMO+Impella (ECPELLA) in each dog. In protocol 2 (n=15), we ligated coronary arteries for 180 min and then reperfused. We activated Impella CP and/or ECMO from 60 min after the coronary ligation to the end of the experiment. We allocated dogs into 3 groups, no support (Control), ECMO, and ECPELLA and compared infarct size at 180 min after reperfusion among 3 groups. Results: In protocol 1, both ECMO and ECPELLA increased arterial pressure compared to Control (Control: 63±9, ECMO: 88±10 and ECPELLA: 97±18 mmHg, p < 0.05), and resolved the CS status. ECPELLA strikingly reduced PVA by 83% relative to Control (1500±326, 2038±357 and 258±182 mmHg*ml, p<0.001). In protocol 2, ECPELLA markedly reduced the infarct size (15±8%) compared to Control (53±7%, p<0.05) and ECMO (39±10%, p<0.05). Conclusions: ECPELLA before reperfusion markedly improved hemodynamics, reduced PVA, and limited infarct size in a dog model of MI with CS. ECPELLA could prevent ECMO-induced LV overload and synergistically exert powerful anti-infarct effects in AMI with CS.

scholarly journals Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

2021 ◽  
Vol 9 ◽  
Author(s):  
Feng Tian ◽  
Ying Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemic Injury ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Myocardial Infarct Size ◽  
Hypoxic Injury

Our previous research has shown that type-2a Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) undergoes posttranscriptional oxidative modifications in cardiac microvascular endothelial cells (CMECs) in the context of excessive cardiac oxidative injury. However, whether SERCA2a inactivity induces cytosolic Ca2+ imbalance in mitochondrial homeostasis is far from clear. Mitofusin2 (Mfn2) is well known as an important protein involved in endoplasmic reticulum (ER)/mitochondrial Ca2+ tethering and the regulation of mitochondrial quality. Therefore, the aim of our study was to elucidate the specific mechanism of SERCA2a-mediated Ca2+ overload in the mitochondria via Mfn2 tethering and the survival rate of the heart under conditions of cardiac microvascular ischemic injury. In vitro, CMECs extracted from mice were subjected to 6 h of hypoxic injury to mimic ischemic heart injury. C57-WT and Mfn2KO mice were subjected to a 1 h ischemia procedure via ligation of the left anterior descending branch to establish an in vivo cardiac ischemic injury model. TTC staining, immunohistochemistry and echocardiography were used to assess the myocardial infarct size, microvascular damage, and heart function. In vitro, ischemic injury induced irreversible oxidative modification of SERCA2a, including sulfonylation at cysteine 674 and nitration at tyrosine 294/295, and inactivation of SERCA2a, which initiated calcium overload. In addition, ischemic injury-triggered [Ca2+]c overload and subsequent [Ca2+]m overload led to mPTP opening and ΔΨm dissipation compared with the control. Furthermore, ablation of Mfn2 alleviated SERCA2a-induced mitochondrial calcium overload and subsequent mito-apoptosis in the context of CMEC hypoxic injury. In vivo, compared with that in wild-type mice, the myocardial infarct size in Mfn2KO mice was significantly decreased. In addition, the findings revealed that Mfn2KO mice had better heart contractile function, decreased myocardial infarction indicators, and improved mitochondrial morphology. Taken together, the results of our study suggested that SERCA2a-dependent [Ca2+]c overload led to mitochondrial dysfunction and activation of Mfn2-mediated [Ca2+]m overload. Overexpression of SERCA2a or ablation of Mfn2 expression mitigated mitochondrial morphological and functional damage by modifying the SERCA2a/Ca2+-Mfn2 pathway. Overall, these pathways are promising therapeutic targets for acute cardiac microvascular ischemic injury.

scholarly journals Pharmacological priming of adipose-derived stem cells promotes myocardial repair

2016 ◽  
Vol 64 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Jana S Burchfield ◽  
Ashley L Paul ◽  
Vishy Lanka ◽  
Wei Tan ◽  
Yongli Kong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Function ◽  
Functional Recovery ◽  
Cardiac Myocyte ◽  
Left Ventricular ◽  
Adipose Derived Stem Cells ◽  
Myocardial Repair ◽  
Myocyte Differentiation

Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.

Isoflurane Preconditions Myocardium Against Infarction via  Activation of Inhibitory Guanine Nucleotide Binding Proteins

2000 ◽  
Vol 92 (5) ◽  
pp. 1400-1407 ◽  
Author(s):  
Wolfgang G. Toller ◽  
Judy R. Kersten ◽  
Eric R. Gross ◽  
Paul S. Pagel ◽  
David C. Warltier
Keyword(s):  
Infarct Size ◽  
Pertussis Toxin ◽  
Myocardial Infarct ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Rate Of Increase ◽  
Gi Protein

Background Isoflurane-induced myocardial protection during ischemia is mediated by adenosine triphosphate-regulated potassium (KATP) channels; however, the intracellular signal transduction cascade responsible for this process has been incompletely evaluated. The authors tested the hypothesis that isoflurane reduces myocardial infarct size through a Gi protein-mediated process. Methods Forty-eight hours after pretreatment with vehicle (0.9% saline) or the Gi protein inhibitor pertussis toxin (10 microg/kg intravenously), barbiturate-anesthetized dogs (n = 43) were instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3-h reperfusion. In four separate groups, vehicle- or pertussis toxin-pretreated dogs were studied with or without administration of 1 minimum alveolar concentration isoflurane. In two additional groups, dogs received the direct KATP channel agonist nicorandil (100 microg/kg bolus and 10 microg x kg-1 x min-1 intravenous infusion) in the presence or absence of pertussis toxin pretreatment. Myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively. Results Isoflurane significantly (P &lt; 0.05) decreased infarct size to 7 +/- 2% of the area at risk compared with control experiments (26 +/- 2%). Pertussis toxin pretreatment alone had no effects on myocardial infarct size (31 +/- 4%) but blocked the beneficial effects of isoflurane (21 +/- 3%). Nicorandil decreased infarct size (11 +/- 2%), but, in contrast to isoflurane, this effect was independent of pertussis toxin pretreatment (11 +/- 1%). Conclusion Isoflurane reduces myocardial infarct size by a Gi protein-mediated mechanism in vivo.

Cyclooxygenase-2 Mediates Ischemic, Anesthetic, and Pharmacologic Preconditioning In Vivo 

2004 ◽  
Vol 100 (3) ◽  
pp. 547-554 ◽  
Author(s):  
Dunbar Alcindor ◽  
John G. Krolikowski ◽  
Paul S. Pagel ◽  
David C. Warltier ◽  
Judy R. Kersten
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Late Phase ◽  
Coronary Artery Occlusion ◽  
Left Ventricular ◽  
Cyclooxygenase 2 ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Cox 2

Background Cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (IPC), but whether this enzyme modulates early IPC, anesthetic-induced preconditioning (APC), or other forms of pharmacologic preconditioning (PPC) is unknown. The authors tested the hypothesis that COX-2 is an essential mediator of IPC, APC, and PPC in vivo. Methods Barbiturate-anesthetized dogs (n = 91) were instrumented for measurement of hemodynamics and randomly assigned to receive IPC (four 5-min coronary occlusions interspersed with 5-min reperfusions), APC (1.0 minimum alveolar concentration of isoflurane for 30 min), or PPC (selective mitochondrial K(ATP) channel opener diazoxide, 2.5 mg/kg intravenous) in the presence or absence of pretreatment with oral aspirin (650 mg), the selective COX-2 inhibitor celecoxib (200 mg), or acetaminophen (500 mg) administered 24, 12, and 2 h before experimentation in 12 separate experimental groups. All dogs were subjected to a 60-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were quantified with triphenyltetrazolium staining and radioactive microspheres, respectively. Myocardial 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, was measured (enzyme immunoassay) in separate experiments (n = 8) before and after isoflurane administration, in the presence or absence of celecoxib. Results No significant differences in baseline hemodynamics or the left ventricular area at risk for infarction were observed between groups. IPC, isoflurane, and diazoxide all decreased myocardial infarct size (9 +/- 1, 12 +/- 2, and 11 +/- 1%, respectively) as compared with control (30 +/- 1%). Celecoxib alone had no effect on infarct size (26 +/- 3%) but abolished IPC (30 +/-3%), APC (30 +/- 3%), and PPC (26 +/- 1%). Aspirin (24 +/- 3%) and acetaminophen alone (29 +/- 2%) did not alter infarct size or abolish APC-induced protection (18 +/- 1 and 19 +/- 1%, respectively). Isoflurane increased myocardial 6-keto-prostaglandin F1alpha to 463 +/- 267% of baseline in the absence but not in the presence (94 +/- 13%) of celecoxib. Conclusions The results indicate that COX-2 is a critical mediator of IPC, APC, and PPC in dogs. The role of cyclooxygenase enzymes as obligatory mediators of myocardial protection produced by diverse preconditioning stimuli may have implications for the clinical use of COX-2 inhibitors.

Multipotent Adult Progenitor Cells (MAPCs) Improve Cardiac Function after Ischemic Injury.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1701-1701
Author(s):  
Jakub Tolar ◽  
Xiahong Wang ◽  
Scott Bell ◽  
Yasuhiro Nakamura ◽  
Ron T. McElmurry ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Fluorescent Protein ◽  
Sleeping Beauty ◽  
Left Ventricular ◽  
Whole Body ◽  
Myocardial Repair ◽  
Surgical Suture ◽  
Injured Myocardium

Abstract MAPCs are pluripotent cells derived from mesenchymal stromal cells (MSCs) in adult bone marrow. In contrast to MSCs, MAPCs differentiate into various lineages of mesodermal, ectodermal and endodermal origin, and contribute to numerous terminally differentiated tissues in the recipients. This capacity is enhanced in the setting of injury, suggesting a possible role of MAPCs in repair and regeneration in disease states. We aimed to investigate the capacity of MAPCs to aid in myocardial repair in hearts with postinfarction remodeling. We reasoned that as MAPCs differentiate to both endothelium and cardiomyocytes in vitro and as engraftment of delivered cells depends on establishing adequate blood flow in the ischemic region, MAPCs may represent the optimal cell type to contribute to both angiogenesis and the parenchymal tissue to regenerate function of injured myocardium. To study engraftment and survival of MAPCs, we labeled adult murine C57BL/6 MAPCs with firefly luciferase and DsRed2 fluorescent protein using non-viral Sleeping Beauty transposons, and injected them into myocardium of C57BL/6 adult mice with acute myocardial infarction (AMI). Mice were anesthetized, intubated and mechanically ventilated using a small-animal respirator. Under a stereomicroscope the heart was accessed via left thoracotomy. The left anterior descending coronary artery was ligated at mid-level between apex and base with a 9-0 surgical suture to produce AMI. Twenty minutes later, intramyocardial injections of labeled MAPCs in saline, or saline alone were administered at five distinct injection sites at boarder zone of AMI (total MAPC dose = 106/mouse). Chest was closed in layers and animals were allowed to recover. Mice were followed with echocardiography and in vivo whole body bioluminescent imaging. Seventy days after AMI, MAPCs recipients (N=6) had significantly less severe left ventricular (LV) dilatation evidenced by a smaller LV end-diastolic and LV end-systolic dimensions when compared to control mice infused with saline (N=4) (average±standard deviation, 4.7±0.2 mm versus 5.3±0.5 mm, p=0.05; and 3.7±0.2 mm versus 4.4±0.6 mm, p=0.03, respectively). In addition, ejection and shortening fractions were significantly higher in MAPC recipients (36±2% versus 30±3%, p=0.004; and 20±1% versus 16±2%, p=0.004, respectively). Luciferase signals emitted from donor MAPCs were easily detectable in MAPC recipients 100 days after MAPC infusion, at which point the animals were harvested. Analyses are ongoing to determine whether MAPCs and their progeny contributed to expansion of coronary vasculature (capillary density), or formed or modified injured myocardial tissue. Alternatively, both populations of repair cells could have been derived from donor (DsRed2+) MAPCs, or donor MAPCs could have provided permissive local environment to recruit recipient cells and enhance endogeneous regeneration. In summary, these findings provide evidence that MAPCs persist long term in injured myocardium and document the potential of MAPCs for improvement of cardiac function after ischemic myocardial injury. Jakub Tolar and Xiaohong Wang contributed equally to this study.

scholarly journals Time course of echocardiographic and electrocardiographic parameters in myocardial infarct in rats

2007 ◽  
Vol 79 (4) ◽  
pp. 639-648 ◽  
Author(s):  
Amarildo Miranda ◽  
Ricardo H. Costa-e-Sousa ◽  
João P.S. Werneck-de-Castro ◽  
Elisabete C. Mattos ◽  
Emerson L. Olivares ◽  
...  
Keyword(s):  
Infarct Size ◽  
Time Course ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Post Surgery ◽  
Coronary Ligation ◽  
Electrocardiographic Parameters ◽  
Electrocardiogram Ecg

In animal models the evaluation of myocardial infarct size in vivo and its relation to the actual lesion found post mortem is still a challenge. The purpose of the current study was to address if the conventional electrocardiogram (ECG) and/or echocardiogram (ECHO) could be used to adequately predict the size of the infarct in rats. Wistar rats were infarcted by left coronary ligation and then ECG, ECHO and histopathology were performed at 1, 7 and 28 days after surgery. Correlation between infarct size by histology and Q wave amplitude in lead L1 was only found when ECGs were performed one day post-surgery. Left ventricular diastolic and systolic dimensions correlated with infarct size by ECHO on day 7 post-infarction. On days 7 and 28 post-infarction, ejection indexes estimated by M-mode also correlated with infarct size. In summary we show that conventional ECG and ECHO methods can be used to estimate infarct size in rats. Our data suggest that the 7-day interval is actually the most accurate for estimation of infarct size by ECHO.

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