Abstract 323: MicroRNA208a Silencing Attenuates Doxorubicin Induced Cardiac Toxicity and Dysfunction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hasahya Tony ◽  
Qiutang Zeng ◽  
Kunwu Yu
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Toxicity ◽  
Heart Function ◽  
Control Groups ◽  
Improve Heart Function ◽  
Myocyte Apoptosis ◽  
And Control ◽  
Subsequent Improvement ◽  
Fractional Shortening

Aims: Salvaging GATA4 expression mitigates doxorubicin-induced myocyte apoptosis and cardiac dysfunction. We investigated if therapeutic silencing of miR-208a, a heart specific microRNA known to target GATA4, could attenuate doxorubicin-induced myocyte apoptosis and improve heart function. Methods: Eight weeks old female Balb/C mice were randomly assigned to Sham, antagomir and Control groups. Antagomir group mice were pre-treated with 50nmols of miR-208a antagomir 4 days prior to giving doxorubicin. At day 0, control and antagomir group got 20mg/kg of doxorubicin while sham mice received phosphate buffered solution. Echocardiography was done at day 7, after which animals were sacrificed, and hearts assessed for apoptosis and expression of miR-208a, GATA4 and Bcl-2 by quantitative PCR. Results: Doxorubicin significantly upregulated miR-208a P=0.008 , downregulated GATA4 P=0.025 , and increased myocyte apoptosis P=0.001. Therapeutic silencing of miR-208a mitigated the doxorubicin-induced increase in miR-208a, P= 0.003 and salvaged GATA4 expression, with noted increase in Bcl-2 levels compared to controls, P=0.033. Doxorubicin significantly increased cardiomyocyte apoptosis P= 0.001, and this effect was attenuated by pretreatment with miR-208a antagomir, P=0.002 (Figure 1A and B). Doxorubicin also caused significant cardiac dysfunction, P=0.005, while antagomir treatment attenuated doxorubicin-induced cardiac dysfunction as assessed by fractional shortening P=0.011 (Figure 1Cand D) Conclusion: Therapeutic silencing of miR-208a salvages GATA4 and attenuates doxorubicin-induced myocyte apoptosis with subsequent improvement in cardiac function.

scholarly journals MicroRNA-208a Silencing Attenuates Doxorubicin Induced Myocyte Apoptosis and Cardiac Dysfunction

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Hasahya Tony ◽  
Kunwu Yu ◽  
Zeng Qiutang
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Therapeutic Potential ◽  
Cardiomyocyte Apoptosis ◽  
Control Groups ◽  
Novel Approach ◽  
Myocyte Apoptosis ◽  
And Control ◽  
Subsequent Improvement ◽  
Doxorubicin Administration

Aims. GATA4 depletion is a distinct mechanism by which doxorubicin leads to cardiomyocyte apoptosis, and preservation of GATA4 mitigates doxorubicin induced myocyte apoptosis and cardiac dysfunction. We investigated a novel approach of attenuating doxorubicin induced cardiac toxicity by silencing miR-208a, a heart specific microRNA known to target GATA4.Methods and Results. Eight-week-old female Balb/C mice were randomly assigned to sham, antagomir, and control groups. Antagomir group were pretreated with miR-208a antagomir 4 days before doxorubicin administration. At day 0, control and antagomir groups received 20 mg/kg of doxorubicin, while sham mice received phosphate buffered solution. Echocardiography was done at day 7, after which animals were sacrificed and hearts harvested and assessed for apoptosis and expression of miR-208a, GATA4, and BCL-2. Doxorubicin significantly upregulated miR-208a, downregulated GATA4, and increased myocyte apoptosis, with resulting decrease in cardiac function. In contrast, therapeutic silencing of miR-208a salvaged GATA4 and BCL-2 and decreased apoptosis, with improvement in cardiac function.Conclusion. Doxorubicin upregulates miR-208a and promotes cardiomyocyte apoptosis, while therapeutic silencing of miR-208a attenuates doxorubicin induced myocyte apoptosis with subsequent improvement in cardiac function. These novel results highlight the therapeutic potential of targeting miR-208a to prevent doxorubicin cardiotoxicity.

Prediction of Poststorage Cardiac Function From Cardioplegic Effluent in an Ex Vivo Porcine Heart Model

2019 ◽  
Vol 2 (4) ◽  
Author(s):  
Benjamin Kappler ◽  
Sjoerd van Tuijl ◽  
Teus J. van Laar ◽  
Dara R. Pabittei ◽  
Marc P. Buijsrogge ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Ex Vivo ◽  
Heart Function ◽  
Laboratory Animals ◽  
Organ Protection ◽  
Isolated Hearts ◽  
Cardiac Functions ◽  
Proactive Measures

Abstract The use of slaughterhouse-based hearts has advantages over hearts obtained from laboratory animals for preclinical testing. However, slaughterhouse hearts have greater variability in cardiac function; this has resulted in a dispute over their actual reproducibility. This study explores the feasibility of examining the cardioplegic effluent during hypothermic cardiac arrest for the presence of biomarkers to predict poststorage heart function of slaughterhouse hearts. This may enable proactive measures to optimize preservation strategies and improve the initial cardiac performance of slaughterhouse heart experiments. Slaughterhouse pig hearts (n = 9; 420 ± 30 g) were arrested and flushed with an additional liter cardioplegia after 1 h. Effluent samples were examined for ammonia, lactate, troponin, and inorganic phosphate. After 2 h, hearts were hemoreperfused in the ex vivo heart platform PhysioHeart™ to restore physiological cardiac functions and to identify correlations between biomarkers and cardiac output. There was a negative correlation between cardiac output of revived hearts and levels of ammonia (r = −0.865; p = 0.002) and lactate (r = −0.763; p = 0.01). No correlation was found between cardiac output and levels of phosphate (r = −0.553; p = 0.12) and troponin (r = −0.367; p = 0.331). The analysis approach to assess cardioplegic biomarkers was feasible and enabled the estimation of the effectiveness of organ protection and cardiac function before reperfusion. Ammonia is a predictor for cardiac dysfunction. Effluent analysis prior to heart revival can uncover poststorage cardiac dysfunction in isolated hearts and may prevent failed experiments while improving reproducibility and standardization.

Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Bianca C Bernardo ◽  
Sally S Nguyen ◽  
Catherine E Winbanks ◽  
Xiao-Ming Gao ◽  
Esther J Boey ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Pressure Overload ◽  
Post Treatment ◽  
Locked Nucleic Acid ◽  
Luciferase Assay ◽  
Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

Abstract 519: Talin is Required for Normal Adult Heart Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshitake Cho ◽  
Ruixia Li ◽  
Ana M Manso ◽  
Robert S Ross
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Development ◽  
Heart Function ◽  
Left Ventricular ◽  
Mass Spectrometry Analysis ◽  
Adult Heart ◽  
Spectrometry Analysis ◽  
Functional Changes

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.

The effect of nuchal umbilical cord on fetal cardiac and cerebral circulation-cross-sectional study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Julia Murlewska ◽  
Oskar Sylwestrzak ◽  
Przemysław Poszwa ◽  
Maria Respondek-Liberska
Keyword(s):  
Middle Cerebral Artery ◽  
Umbilical Cord ◽  
Cerebral Artery ◽  
Gestational Age ◽  
Cerebral Circulation ◽  
Fetal Heart ◽  
Heart Function ◽  
Control Groups ◽  
Tei Index ◽  
And Control

Abstract Objectives The subject of our analysis is the influence of umbilical cord collision around the fetal neck on the fetal heart function and cerebral circulation. Methods Our study was carried out on a group of 115 fetuses from single pregnancies with physiological course, during the 15th to 40th week of pregnancy. In our analysis, we examined the following parameters: Tei index for right ventricle, Tei index for left ventricle with Tei index components: isovolumetric contraction time, isovolumetric relaxation time, ejection time and cardiothoracic area ratio, middle cerebral artery peak systolic velocity (PS MCA), middle cerebral artery pulsatility index (PI MCA). Gestational age in our study was: 28+2±34. The study group of patients with fetal umbilical cord around neck group (fUCAN) included 38 fetuses (20 males, 18 females). The control group of patients with no fetal umbilical cord around neck group (NfUCAN) included 77 fetuses (43 males, 34 females). Results In our study, we found no significant differences in the values obtained: Tei LV in fUCAN: 0.5±0.1 vs. in NfUCAN: 0.5±0.1; p=0.42), Tei RV in fUCAN: 0.5±0.2 vs. in NfUCAN: 0.4±0.1; (p=0.2). Tricuspid valve regurgitation-TR was observed with the following frequency: fUCAN: 7/38, 18% vs. NfUCAN: 13/77, 17%; p=0.8. MCA PS in study fUCAN group was significantly higher than in NfUCAN (40.2±11.5 vs. 32.5±9.5; p=0.003), although other hemodynamic and clinical variables did not differ between the study and control groups. Conclusions The fetal nuchal umbilical cord collision did not affect the fetal heart function expressed as Tei index, at the time of fetal heart examination (at mean gestational age 29+4 weeks). The fUCAN group presented elevated PS MCA, which was not related to other hemodynamic and clinical variables between the study and control groups.

Abstract 12464: Exosomes Loaded With Microrna-126 Prevents Sepsis-induced Cardiac Dysfunction in Endothelial Cell Hspa12b Deficient Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Xia Zhang ◽  
Xiaohui Wang ◽  
Tuanzhu Ha ◽  
Li Liu ◽  
He Ma ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Vascular Permeability ◽  
Adhesion Molecules ◽  
Cardiac Dysfunction ◽  
Immune Cell ◽  
Cecal Ligation ◽  
Protective Role ◽  
The Right ◽  
Fractional Shortening

We have previously shown that increased expression of endothelial heat shock protein A12B (HSPA12B) attenuates LPS-induced cardiac dysfunction. MicroRNA-126 (miR-126) specifically targets adhesion molecules in endothelial cells. This study examined the role of miR-126 in HSPA12B-induced cardioprotection in sepsis. Endothelial HSPA12B-/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgery served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 h after CLP. CLP sepsis significantly decreased ejection fraction (EF%) by 34.8% and fractional shortening (%FS) by 43.1% in WT mice. EF% and FS% values in HSPA12B-/- septic mice showed further decreases of 19.9% and 22.5% compared with WT septic mice. The levels of ICAM1 and VCAM1 and the infiltration of immune cells (macrophages and neutrophils) into the myocardium of HSPA12B-/- septic mice were markedly greater than WT septic mice. The vascular permeability in HSPA12B-/- septic mice was much more severe than in WT septic mice. Importantly, the levels of circulating miR-126 in HSPA12B-/- septic mice were much lower than in WT septic mice. To examine whether decreased miR-126 is responsible for cardiac dysfunction in HSPA12B-/- septic mice, we loaded exosomes with miR-126 by transfection of bone marrow stromal cells with miR-126 mimics followed by isolation of exosomes 24 hours after transfection. Scrambled miR served as the miR control (miR-control). Exosomes loaded with miR-126 or miR-control were delivered into the myocardium through the right carotid artery immediately after induction of CLP (n=5-6/group). Cardiac function was significantly improved by delivery of miR-126 into the myocardium as evidenced by increased the values of EF% (51%) and FS% (59%), when compared with HSPA12B-/- septic mice. MiR-126 delivery significantly suppressed the expression of adhesion molecules, reduced immune cell infiltration in the myocardium, and improved vascular permeability in HSPA12B-/- septic mice. Delivery of miR-control did not alter cardiac dysfunction in HSPA12B-/- septic mice. We conclude that miR-126 plays a critical protective role in endothelial HSAP12B in preservation of cardiac function in sepsis.

Hypertriglyceridemia in experimental diabetes: relationship to cardiac dysfunction

1994 ◽  
Vol 72 (5) ◽  
pp. 447-455 ◽  
Author(s):  
Brian Rodrigues ◽  
Paul F. Grassby ◽  
Mary L. Battell ◽  
Stephanie Y. N. Lee ◽  
John H. McNeill
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Plasma Triglyceride ◽  
Diabetic Rat ◽  
Diabetic Patients ◽  
Beneficial Effects ◽  
Rate Of Increase

The incidence of mortality from cardiovascular disease is higher in diabetic patients. The objective of the present investigation was to test die hypothesis that the diabetes-induced depression in cardiac function may be due to hypertriglyceridemia. Hyperlipidemia and a depressed left ventricular developed pressure and rate of increase and decrease of ventricular pressure (±dP/dt) were produced in isolated hearts from rats made diabetic with streptozotocin compared with hearts from control animals. This depressed cardiac performance was successfully prevented by hydralazine treatment (for 3 weeks), which also lowered plasma triglyceride levels and suggested that hyperlipidemia may be important in altering cardiac function in experimental diabetic rats. The beneficial effects of clofibrate, verapamil, prazosin, enalapril, and benazepril administration were then studied in diabetic rats. The treatments (with die exception of enalapril) significantly reduced plasma triglyceride levels but did not prevent die onset of heart dysfunction in chronically diabetic rats. These studies suggest that in the chronically diabetic rat, hypertriglyceridemia may not be as important as previously suggested, in the development of cardiac dysfunction. Since acute dichloroacetate perfusion improves cardiac function in 6 week (but not 24 week) diabetic rats, it appears more likely that improving myocardial glycose utilization is more critical than triglyceride lowering, in preventing cardiac dysfunction in die diabetic rat at this time point.Key words: diabetes, triglycerides, heart function, glucose oxidation.

scholarly journals Exogenous ubiquitin reduces inflammatory response and preserves myocardial function 3 days post-ischemia-reperfusion injury

2019 ◽  
Vol 316 (3) ◽  
pp. H617-H628 ◽  
Author(s):  
Stephanie L. C. Scofield ◽  
Suman Dalal ◽  
Kristina A. Lim ◽  
Patsy R. Thrasher ◽  
Christopher R. Daniels ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Adrenergic Receptor ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Group Versus ◽  
Protective Role ◽  
Area At Risk ◽  
Myocyte Apoptosis ◽  
Fractional Shortening

β-Adrenergic receptor (β-AR) stimulation increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases β-AR-stimulated myocyte apoptosis and myocardial fibrosis. Here, we hypothesized that exogenous UB modulates the inflammatory response, thereby playing a protective role in cardiac remodeling after ischemia-reperfusion (I/R) injury. C57BL/6 mice infused with vehicle or UB (1 μg·g−1·h−1) were subjected to myocardial I/R injury. Functional and biochemical parameters of the heart were examined 3 days post-I/R. Heart weight-to-body weight ratios were similarly increased in I/R and UB + I/R groups. The area at risk and infarct size were significantly lower in UB + I/R versus I/R groups. Measurement of heart function using echocardiography revealed that I/R decreases percent fractional shortening and percent ejection fraction. However, the decrease in fractional shortening and ejection fraction was significantly lower in the UB + I/R group. The UB + I/R group displayed a significant decrease in inflammatory infiltrates, neutrophils, and macrophages versus the I/R group. Neutrophil activity was significantly lower in the UB + I/R group. Analysis of the concentration of a panel of 23 cytokines/chemokines in the serum using a Bio-Plex assay revealed a significantly lower concentration of IL-12 subunit p40 in the UB + I/R versus I/R group. The concentration of monocyte chemotactic protein-1 was lower, whereas the concentration of macrophage inflammatory protein-1α was significantly higher, in the UB+I/R group versus the sham group. Expression of matrix metalloproteinase (MMP)-2 and activity of MMP-9 were higher in the UB + I/R group versus the I/R group. Levels of ubiquitinated proteins and tissue inhibitor of metalloproteinase 2 expression were increased to a similar extent in both I/R groups. Thus, exogenous UB plays a protective role in myocardial remodeling post-I/R with effects on cardiac function, area at risk/infarct size, the inflammatory response, levels of serum cytokines/chemokines, and MMP expression and activity.NEW & NOTEWORTHY Stimulation of β-adrenergic receptors increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases β-adrenergic receptor-stimulated myocyte apoptosis and myocardial fibrosis. Here, we provide evidence that exogenous UB decreases the inflammatory response and preserves heart function 3 days after myocardial ischemia-reperfusion injury. Further identification of the molecular events involved in the anti-inflammatory role of exogenous UB may provide therapeutic targets for patients with ischemic heart disease.

Effects of free fatty acids and dichloroacetate on isolated working diabetic rat heart

1991 ◽  
Vol 261 (4) ◽  
pp. H1053-H1059 ◽  
Author(s):  
T. A. Nicholl ◽  
G. D. Lopaschuk ◽  
J. H. McNeill
Keyword(s):  
Fatty Acids ◽  
Heart Rate ◽  
Cardiac Function ◽  
Free Fatty Acids ◽  
Cardiac Dysfunction ◽  
Glucose Oxidation ◽  
Heart Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Diabetic Heart

It is well established that cardiac dysfunction independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology is complex, involving many different processes, one of which may be increased fatty acid utilization and/or a concomitant decrease in glucose utilization by the diabetic heart. We compared control and 6-wk streptozotocin (STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR.PSP), left ventricular developed pressure (LVDP), and rate of pressure rise (+dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia, and decreased body weight gain compared with age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts. But diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. HR and HR.PSP in spontaneously beating hearts, as well as LVDP and +dP/dt in paced hearts were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and ATP levels were similar under all perfusion conditions, thus eliminating energy stores as the limiting factor in heart function. Results indicate that DCA will acutely reverse diabetic cardiac function depression. Therefore glucose oxidation depression in the diabetic heart may be a significant factor contributing to cardiac dysfunction.

Abstract 13427: Extracellular Vesicles Improve Heart Function Without Inducing the Generation of New Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Bruna Lima Correa ◽  
Nadia El harane ◽  
Maria Perotto ◽  
Manon Desgres ◽  
Chloe Guillas ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Extracellular Vesicles ◽  
De Novo ◽  
Heart Function ◽  
Heart Tissue ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Heart Repair ◽  
Significant Difference ◽  
Improve Heart Function

Introduction: Extracellular Vesicles (EV) recapitulate the benefits of cell therapy for heart repair. Their mechanism of action remains unsettled. Hypothesis: EV may contribute to heart repair by de novo cardiogenesis. Methods: To answer this question, we used 2 bi-transgenic mouse models: the fate-mapping MerCreMer/ZEG and the Mosaic Analysis With Double Markers (MADM). Myocardial infarction was induced by permanent coronary artery ligation. Those with a LVEF ≤ 45% were treated 3 weeks later with EV (from human iPS-derived cardiovascular progenitor cells; 10x10 9 particles) or PBS, injected under echo guidance in the peri-infarcted area (MerCreMer/ZEG: n=15/group and MADM: n=6/group). To track endogenous cardiomyocyte (CM) proliferation, we used EdU labeling in MerCreMer/ZEG delivered by osmotic pumps implanted for 7-10 days post-injection and biphoton microscopy in MADM models. Cardiac function was assessed 4-6 weeks after injection by echocardiography and MRI, blinded to treatment group. Hearts were then subjected to histological and transcriptomic analyses (qPCR and genome-wide microarray). Results: In PBS controls, EF remained stable over time in MerCreMer/ZEG mice and decreased from 34.5% ± 6.0% to 30.7% ± 7.5% in MADM mice by the end of the study. Conversely, EV injections increased EF from 32.1% ± 9.5% to 36.1% ± 7.45 % in MerCreMer/ZEG and from 36.2 %± 8.7% to 40.5% ± 8.9% in MADM mice. A significant difference in the change from baseline was found between EV and controls: 20.7% ± 10.5 % (p=0.048) and 28.0% ± 11.0 %, (p=0.045) for MerCreMer/ZEG and MADM groups, respectively. This improvement was confirmed by MRI in MerCreMer/ZEG mice (p=0.05). Improvement in EF was unrelated to the appearance of new CM, as shown by the absence of difference in TnT+/EdU+/GFP+ cell numbers and the lack of activation of the YAP/TAZ pathway between control and EV groups. However, EV reduced infarct size by 11.9% ± 5.75% (p=0.04), which was accompanied by decreased expression of 4 pro-fibrotic genes (Col1a2, Col3a1, Lox, Col1a2 by qPCR) in heart tissue and a 2.13X overexpression of the anti-fibrotic miRNA 133a-1 compared to controls (n=3/group; p=0.001). Conclusions: EV likely improve cardiac function by modulation of fibrosis rather than by de novo cardiogenesis.

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