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.

scholarly journals Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

2017 ◽  
Vol 114 (7) ◽  
pp. 1649-1654 ◽  
Author(s):  
Jesung Moon ◽  
Huanyu Zhou ◽  
Li-shu Zhang ◽  
Wei Tan ◽  
Ying Liu ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Anticancer Agents ◽  
Heart Function ◽  
Heart Tissue ◽  
Coronary Artery Ligation ◽  
Collagen Vi ◽  
Artery Ligation ◽  
Wnt Proteins ◽  
Infarcted Heart

The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

Abstract 402: Vitamin C Deficiency Impairs Cardiac Function and Post-infarction Survival in the Mouse

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Adolfo G Mauro ◽  
Donatas Kraskauskas ◽  
Bassem M Mohammed ◽  
Bernard J Fisher ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Vitamin C ◽  
Cardiac Function ◽  
Diastolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Additional Group ◽  
Gulonolactone Oxidase ◽  
Low Levels ◽  
Systolic And Diastolic Function

Introduction: L-gulonolactone oxidase (Gulo) is the rate limiting enzyme for Vitamin C (VitC) biosynthesis. Humans rely on dietary VitC for collagen synthesis, extracellular matrix formation, and tissue regeneration. VitC deficiency is an unrecognized condition and its role in cardiac homeostasis and post-acute myocardial infarction (AMI) remodeling is unknown. Hypothesis: Low levels of VitC impair cardiac function and tissue repair following AMI. Methods: Adult male Gulo -/- knockout mice (C57BL6 background, N=8) and control C57BL (N=8), which are able to synthesize VitC were used. VitC deficiency was maintained supplying low levels of VitC (30mg/l) to Gulo -/- mice in drinking water. Mice underwent M-mode and Doppler echocardiography to measure left ventricular (LV) diameters and wall thicknesses, fractional shortening (FS), E and A waves, E/A ratio, isovolumetric relaxation time (IRT) and myocardial performance index (MPI). Experimental AMI was induced by coronary artery ligation for 7 days. An additional group of Gulo -/- were mice supplemented with physiological levels of VitC (330 mg/l) and underwent AMI. Results: VitC deficient Gulo -/- mice exhibited significantly reduced LV wall thicknesses, reduced FS, and impaired diastolic function, measured as significantly reduced E/A ratio and longer IRT (Panel A, B & C). Following AMI, 100% (8/8) of deficient Gulo -/- mice died within 5 days. Supplementation with physiological levels of VitC significantly improved survival after AMI (Panel D). Conclusion: VitC deficiency impairs systolic and diastolic function. Moreover, VitC is critical for the post-AMI survival.

scholarly journals PO-301 Study on the effects of bone marrow-derived stem cells were used in chronic hyperactivity rats to cardiac injury treatment

2018 ◽  
Vol 1 (5) ◽  
Author(s):  
Lei Xu ◽  
YiBo Niu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cardiac Function ◽  
Test Data ◽  
Cardiac Tissue ◽  
Heart Function ◽  
Training Group ◽  
Significant Difference ◽  
General Training

Objective  overload and long-term overtraining can cause hypoxic and hypoxic damage to the myocardial structure of the body. In recent years, studies have shown that the stem cells promote angiogenesis in vivo, resistance to apoptosis, myocardial stem cell mobilization, and promote its proliferation in paracrine effect, such as vascular distribution. By animal experiments, this study explore MSCMs role in the improvement of heart function and its molecular mechanism to sports injury prevention and postoperative rehabilitation is of great significance of the heart, heart research provides the basis for the motion at the same time support. Methods Wistar rat model of excessive swimming training. Grouping: rats were randomly divided into 4 groups (n=10), quiet feeding group (Q), general training group (ET), over-training group (OT), and MSCMs transplant-over-training group (MOT). Source and preparation of stem cells: the rat autologous bone marrow was extracted 1 day before surgery, and the bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. Methods of stem cell transplantation: perfusion via coronary artery in MOT group rats; Test indicators and methods: cardiac tissue was taken after the end of 1d training (group Q, ET and OT), MEF2A factor was tested by rcal-time, gata-4 expression was tested by Western blot, and LVEF value was observed by cardiac color doppler ultrasound (before, after 1w, after 2w and after 3w, respectively). Results MEF2A factor, gata-4 expression and LVEF value of the three groups of samples were detected: (1) compared with MEF2A factor in general training group (ET) and quiet group (Q), gata-4 expression was slightly improved, but there was no significant difference (P>0.05). After 3w, the increase of LVEF value presented significant differences (Pwhile 1w and 2w showed no significant differences compared with the quiet group. (2) comparison between the over-training group (OT) and the quiet group (Q) showed significant differences in MEF2A factor, gata-4 expression, and LVEF decreased value (P0.05) between the two groups after 2w and the quiet group (Q). Cardiac tissue was taken after 2w to observe the expression of MEF2A, and gata-4 was compared with the silent group (Q) without significant difference (P>0.05). Conclusions (1) based on the test data of general training group (ET), reasonable and scientific aerobic exercise can effectively enhance the cardiac function and improve the cardiac activity ability. (2) according to the test data of over-training group (OT), overloading and long-term over-training can lead to hypoxia of heart function and decrease of vitality, resulting in hypoxia and ischemia of the motor heart and damage of cardiac function. (3) according to the observation and test data of the MSCMs transplant-over-training group (MOT), MSCMs transplantation can effectively improve the cardiac function of sports injuries, enhance the cardiac vitality, and repair damaged cells and tissues to a certain extent. It can effectively prevent and treat heart injury caused by overtraining. At the same time, it provides animal experimental research support for the research of sports heart in sports medicine.

Effects of carbon nanotube-mediated Caspase3 gene silencing on cardiomyocyte apoptosis and cardiac function during early acute myocardial infarction

Nanoscale ◽  
2020 ◽  
Vol 12 (42) ◽  
pp. 21599-21604
Author(s):  
Yi Li ◽  
Hong Yu ◽  
Liang Zhao ◽  
Yuting Zhu ◽  
Rui Bai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Gene Silencing ◽  
Ventricular Remodeling ◽  
Myocardial Cell ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Sd Rats

Caspase3 gene silencing based on the gene transfer carrier F-CNT-siCas3 had obvious protective effects on myocardial cell apoptosis, ventricular remodeling, and cardiac function in Sprague-Dawley (SD) rats after coronary artery ligation.

Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943

2003 ◽  
Vol 284 (3) ◽  
pp. H903-H910 ◽  
Author(s):  
William P. Magee ◽  
Gayatri Deshmukh ◽  
Michael P. Deninno ◽  
Jill C. Sutt ◽  
Justin G. Chapman ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Recovery Of Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Negative Effects ◽  
Artery Ligation ◽  
Regional Ischemia ◽  
Developed Pressure ◽  
Postischemic Recovery

KB-R7943 and SEA0400 are Na+/Ca2+ exchanger (NCX) inhibitors with differing potency and selectivity. The cardioprotective efficacy of these NCX inhibitors was examined in isolated rabbit hearts (Langendorff perfused) subjected to regional ischemia (coronary artery ligation) and reperfusion. KB-R7943 and SEA0400 elicited concentration-dependent reductions in infarct size (SEA0400 EC50: 5.7 nM). SEA0400 was more efficacious than KB-R7943 (reduction in infarct size at 1 μM: SEA0400, 75%; KB-R7943, 40%). Treatment with either inhibitor yielded similar reductions in infarct size whether administered before or after regional ischemia. SEA0400 (1 μM) improved postischemic recovery of function (±dP/d t), whereas KB-R7943 impaired cardiac function at ≥1 μM. At 5–20 μM, KBR-7943 elicited rapid and profound depressions of heart rate, left ventricular developed pressure, and ±dP/d t. Thus the ability of KB-R7943 to provide cardioprotection is modest and limited by negative effects on cardiac function, whereas the more selective NCX inhibitor SEA0400 elicits marked reductions in myocardial ischemic injury and improved ±dP/d t. NCX inhibition represents an attractive approach for achieving clinical cardioprotection.

New insights into the pathological role of TNF-α in early cardiac dysfunction and subsequent heart failure after infarction in rats

2004 ◽  
Vol 287 (1) ◽  
pp. H340-H350 ◽  
Author(s):  
C. Berthonneche ◽  
T. Sulpice ◽  
F. Boucher ◽  
L. Gouraud ◽  
J. de Leiris ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Pressure ◽  
Subsequent Development ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Direct Role ◽  
Volume Curve ◽  
Tnf Α

A marked increase in plasma TNF-α has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-α receptor type II (sTNF-RII, 40 μg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-α, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI ( P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-α plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

2005 ◽  
Vol 288 (5) ◽  
pp. H2491-H2497 ◽  
Author(s):  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mineralocorticoid Receptors ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function ◽  
Adrenoceptor Agonist ◽  
The Brain

In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng·kg−1·h−1) or its vehicle, or with benzamil (4 μg·kg−1·h−1) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the α2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (∼31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.

Abstract 368: Biomechanical Properties of Scar ECM: from the Acute to Chronic Stages of Myocardial Infarction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Bryn Brazile ◽  
J. R Butler ◽  
Sourav Patnaik ◽  
Yanyi Xu ◽  
Andrew Claude ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Function ◽  
Sodium Dodecyl ◽  
Longitudinal Direction ◽  
Biomechanical Properties ◽  
Circumferential Direction ◽  
Heart Cell ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Biaxial Behavior

Introduction: Myocardial infarction (MI) affects more than 8 million Americans, causing massive heart cell death and heart function decrease. To better understand the scar biomechanics, we characterized the mechanical properties of pure scar ECM, obtained by decellularizing the MI tissues. Materials and Methods: Infarcted rat hearts were generated by a permanent left coronary artery ligation (PLCAL) and harvested at 15 min, 1, 2, and 4 weeks (per acute to chronic stages of MI)(N = 6 each). Scar ECM were obtained by decellularizing the infarcted hearts in 0.1% sodium dodecyl sulfate (SDS) solution for 3 weeks. Scar ECM specimens were trimmed into square shape, and then subjected to biaxial testing with one edge aligned with the circumferential direction and the other edge aligned with the longitudinal direction of the rat heart. After 10 cycle preconditioning, an equibiaxial tension protocol of T circ : T rad = 30:30 N/m was performed to capture the tissue biaxial behavior. Results and Discussion: Scar ECM 15 minutes through 4 weeks post infarction showed a stiffening biaxial behavior along with the time (Fig.1). The decrease of extensibility along longitudinal direction was more noticeable than circumferential direction, which led to a decrease in degree of anisotropy. Conclusions: Scar ECM biomechanics showed a stiffening behavior with a marked reduction in extensibility (longitudinal) with time. This change in biomechanical properties can be correlated to the collagen structure changes with progression of MI. Knowledge of the structural-mechanical relationship of scar ECM will help us understand MI progression and help formulate regenerative therapies.

scholarly journals β1-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction

2009 ◽  
Vol 297 (4) ◽  
pp. H1377-H1386 ◽  
Author(s):  
ByungSu Yoo ◽  
Anthony Lemaire ◽  
Supachoke Mangmool ◽  
Matthew J. Wolf ◽  
Antonio Curcio ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Border Zone ◽  
Tunel Staining ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cardiac Inotropy ◽  
Significant Attenuation

The β-adrenergic receptor (βAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca2+ homeostasis. We investigated the role of βAR stimulation in augmenting cardiac function and its role in the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) using various βAR knockouts (KO) including β1ARKO, β2ARKO, and β1/β2AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific βAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in β1ARKO and DKO compared with either the β2ARKO or wild-type (WT) mice, indicating that β1ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), β1ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the β2ARKO or WT mice. CaMKII activity after MI was significantly increased only in the β2ARKO and WT hearts and not in the β1ARKO and DKO hearts. The border zone of the infarct in the β2ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the β1ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the β1AR. Moreover, it appears that β1AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

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