Abstract 5572: Endothelial-Selective Deletion of Neuregulin-1 Leads to Impaired Tolerance of Ischemic Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Qunhua Huang ◽  
April Kalinowski ◽  
Kashif Jafri ◽  
Monica Palmeri ◽  
Raymond R Russell ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Glucose Uptake ◽  
Cardiac Myocyte ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Left Ventricular ◽  
Neuregulin 1 ◽  
Compound C

The neuregulin-1 (NRG)/erbB signaling axis is emerging as an important mediator of endothelial/myocyte crosstalk. We have previously shown that NRG can protect cardiac myocytes from apoptosis induced by hypoxic injury and that endothelial cells can provide this NRG in an ex vivo co-culture model. To extend this observation to an intact animal system, we have generated mice with inducible and endothelial-selective deletion of NRG. We hypothesized that animals with decreased endothelial NRG expression would be more susceptible to ischemic injury. Mice carrying a transgene for tamoxifen-inducible expression of cre recombinase under control of the Tie2 promoter were crossed with those carrying homozygously floxed NRG-1 genes. Serial echocardiographic measurements of cardiac function were performed before, during and after tamoxifen induction. There was no significant decrease in cardiac function following the completion of the induction (NRG knockout) protocol. Hearts from these mice underwent a global ischemia/reperfusion protocol in the Langendorff mode. Both resting and post-ischemic +/−dP/dT and left ventricular developed pressure were impaired in the animals with endothelial selective NRG deletion compared to non-induced transgenics or tamoxifen-induced controls. Hearts from the NRG deleted animals released more CPK and contained significantly more apoptotic nuclei compared to controls after ischemia/reperfusion, supporting the idea that endothelial-derived NRG can protect myocytes against apoptosis in vivo. Another mechanism by which loss of NRG may contribute to cardiac dysfunction in the setting of ischemia is by altering cardiac myocyte glucose uptake. We have shown that adult rat cardiomyocyte glucose uptake is significantly increased in response to NRG and that this response is abrogated partially by wortmannin, but completely by wortmannin plus compound C (an inhibitor of AMP-activated protein kinase), suggesting that both AKT and AMPK dependent pathways of glucose uptake may be activated by NRG in adult myocytes. Thus, we conclude that NRG plays an important role in preservation of cardiac myocyte function in vivo and that this may occur as a result of both protection against apoptosis and enhanced glucose metabolism.

Abstract 122: Cardiac mTOR Preserves Cardiac Function Following Ex Vivo Ischemia-Reperfusion in Diet-Induced Obese Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Toshinori Aoyagi ◽  
Takashi Matsui
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Cardiac Function ◽  
Glucose Intolerance ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Weight ◽  
Diabetic Patients ◽  
Significant Difference

The risk of heart failure following myocardial infarction is higher in diabetic patients than nondiabetic patients. The mammalian target of rapamycin (mTOR), a key downstream molecule of insulin-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, plays an important role in cardioprotection. However, the role of cardiac mTOR in ischemic injury in metabolic syndrome has not been well defined. To address this question, we studied the effect of overexpressing cardiac mTOR on cardiac function following ischemia/reperfusion (I/R) in mice with high-fat diet (HFD)-induced obesity. In this study, we used transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) as reported previously. mTOR-Tg and WT mice at 6 weeks old were fed HFD (60% fat by calories) ad libitum for 14 weeks. Control mTOR-Tg and WT mice were fed a normal chow diet (NCD). At 14 weeks after HFD, glucose and insulin tolerance tests demonstrated that HFD generated glucose intolerance and insulin resistance in both mTOR-Tg (n=20) and WT (n=24) mice. Body weight (BW) and heart weight (HW) were significantly higher in HFD mice than SCD mice (p<0.001 for BW in both strains; p<0.001 and p<0.01 for HW/tibia length, WT and mTOR-Tg, respectively) but there was no difference in BW or HW between HFD-mTOR-Tg and HFD-WT mice. Hearts from all four groups were subjected to global I/R (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. Baseline left ventricular developed pressure (LVDP) was higher in HFD mice than NCD mice in both strains [185.8 ± 10.7 vs. 143.6 ± 5.0 mmHg, HFD-WT (n=11) vs. NCD-WT (n=10) mice, p<0.01; 178.6 ± 10.1 vs. 135.0 ± 6.3, HFD-mTOR-Tg (n=8) vs. NCD-mTOR-Tg (n=11) mice, p<0.01]. Functional recovery after I/R was significantly lower in HFD-WT mice than NCD-WT mice (percent recovery of LVDP, 15.3 ± 5.4 vs. 44.6 ± 6.3 %, HFD-WT vs. NCD-WT mice, p<0.01). Intriguingly, there was no significant difference in LVDP recovery between HFD-mTOR-Tg and NCD-mTOR-Tg mice (36.5±10.8 vs. 58.8±6.0 %, HFD-mTOR-Tg vs. NCD-mTOR-Tg mice, n.s.). These findings suggest that cardiac mTOR is sufficient to substantially limit the metabolic syndrome-induced cardiac dysfunction following I/R in a mouse model of obesity with glucose intolerance and insulin resistance.

scholarly journals Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

2015 ◽  
Vol 308 (12) ◽  
pp. H1530-H1539 ◽  
Author(s):  
Toshinori Aoyagi ◽  
Jason K. Higa ◽  
Hiroko Aoyagi ◽  
Naaiko Yorichika ◽  
Briana K. Shimada ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Chow Diet ◽  
In Vivo Models ◽  
Myocardial Scarring ◽  
Diet Induced Obesity ◽  
Normal Chow ◽  
Normal Chow Diet

Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring.

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.

Co-expression of skeletal and cardiac troponin T decreases mouse cardiac function

2008 ◽  
Vol 294 (1) ◽  
pp. C213-C222 ◽  
Author(s):  
Q.-Q. Huang ◽  
H. Z. Feng ◽  
J. Liu ◽  
J. Du ◽  
L. B. Stull ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Troponin T ◽  
Ex Vivo ◽  
Heart Function ◽  
Left Ventricular Pressure ◽  
Experimental System ◽  
Left Ventricular ◽  
Negative Effects

In contrast to skeletal muscles that simultaneously express multiple troponin T (TnT) isoforms, normal adult human cardiac muscle contains a single isoform of cardiac TnT. To understand the significance of myocardial TnT homogeneity, we examined the effect of TnT heterogeneity on heart function. Transgenic mouse hearts overexpressing a fast skeletal muscle TnT together with the endogenous cardiac TnT was investigated in vivo and ex vivo as an experimental system of concurrent presence of two classes of TnT in the adult cardiac muscle.This model of myocardial TnT heterogeneity produced pathogenic phenotypes: echocardiograph imaging detected age-progressive reductions of cardiac function; in vivo left ventricular pressure analysis showed decreased myocardial contractility; ex vivo analysis of isolated working heart preparations confirmed an intrinsic decrease of cardiac function in the absence of neurohumoral influence. The transgenic mice also showed chronic myocardial hypertrophy and degeneration. The dominantly negative effects of introducing a fast TnT into the cardiac thin filaments to produce two classes of Ca2+ regulatory units in the adult myocardium suggest that TnT heterogeneity decreases contractile function by disrupting the synchronized action during ventricular contraction that is normally activated as an electrophysiological syncytium.

Cardiac responses of rats submitted to postnatal protein restriction

2012 ◽  
Vol 37 (3) ◽  
pp. 455-462 ◽  
Author(s):  
Tatiane Moisés Murça ◽  
Tatiana Soares dos Reis Magno ◽  
Marilda Luz de Andrade De Maria ◽  
Carolina Andrade Bragança Capuruço ◽  
Deoclécio Alves Chianca ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ex Vivo ◽  
Isolated Heart ◽  
Left Ventricular ◽  
Current Data ◽  
Protein Restriction ◽  
Fiber Density ◽  
Arterial Blood ◽  
Male Wistar Rats

Undernutrition during critical stages of development and childhood has important effects on cardiovascular homeostasis. The present study was undertaken to evaluate the in vivo and ex vivo cardiac function of rats submitted to postnatal protein restriction. Male Wistar rats (28 days old) were fed a regular (20%) or low-protein (6%) diet over 5 weeks. After this period, cardiac function was analyzed by echocardiography and isolated heart preparation. Furthermore, the density of cardiac noradrenergic fibers and hematological profile were evaluated. We found that malnourished rats exhibited elevated arterial blood pressure, increased fractional shortening (echocardiography), increased systolic tension, increased ±dT/dt (isolated heart technique), impaired diastolic function characterized by a slight increase in the left ventricular end-diastolic diameter (echocardiography) and decreased diastolic tension (isolated heart technique), and cardiac hypertrophy evidenced by augmentation of the posterior left ventricular wall and discrete hematological changes. In addition, malnourished rats exhibited increased noradrenergic fiber density in their hearts (0.08% ± 0.02% area in control rats vs. 0.17% ± 0.03% area in malnourished rats). Our current data demonstrate that postnatal protein restriction causes cardiac adaptation characterized by an early overworking heart. This is at least in part mediated by an increase in the efferent sympathetic fibers to the heart. These findings provide important information for efforts to prevent and manage the consequences of undernutrition in the human population.

Abstract 1856: Transplantation of Bone-marrow Mononuclear Cells into the Infarcted Heart has Favorable Engraftment Compared to Mesenchymal Stem Cells, Skeletal Myoblasts and Fibroblasts

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Koen E van der Bogt ◽  
Ahmad Y Sheikh ◽  
Sonja Schrepfer ◽  
Grant Hoyt ◽  
Feng Cao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Function ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Donor Cell ◽  
Cell Number ◽  
Left Ventricular ◽  
Skeletal Myoblasts

Introduction: A comparative analysis of the efficacy of different cell candidates for the treatment of heart disease remains to be described. This study aimed to evaluate the therapeutic efficacy of 4 cell types in a murine model of myocardial infarction. Methods: Bone-marrow cells (MN), mesenchymal cells (MSC), skeletal myoblasts (SkMb) and fibroblasts (Fibro) were isolated from male L2G transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Cells were characterized by flow cytometry, bioluminescence imaging (BLI), and luminometry. Female FVB mice (n=60) underwent LAD ligation and were randomized into 5 groups to intramyocardially receive one cell type (5 × 10 5 ) or PBS. Cell survival was measured in vivo by BLI and ex vivo by TaqMan PCR at week 6. Cardiac function was assessed by echocardiography and invasive hemodynamic measurements at week 6. Results: Fluc expression correlated with cell number in all groups (r 2 >0.93). In vivo BLI revealed donor cell death of MSC, SkMb, and Fibro within 3 weeks after transplantation. By contrast, cardiac signal was still present after 6 weeks in the MN group, as confirmed by PCR (p<0.01). Echocardiography showed significant preservation of fractional shortening in the MN group compared to controls (p<0.05). Measurements of left ventricular end-systolic/diastolic volume revealed the least amount of ventricular dilatation occurred in the MN group (p<0.05). Conclusion: This is the first study to directly compare a variety of cell candidates for myocardial therapy and indicates that MN exhibit a favorable survival pattern, which translates into preservation of cardiac function.

scholarly journals Magnetic resonance-compatible model of isolated working heart from large animal for multimodal assessment of cardiac function, electrophysiology, and metabolism

2016 ◽  
Vol 310 (10) ◽  
pp. H1371-H1380 ◽  
Author(s):  
Fanny Vaillant ◽  
Julie Magat ◽  
Pierre Bour ◽  
Jérôme Naulin ◽  
David Benoist ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Cardiac Function ◽  
Electromechanical Coupling ◽  
Ex Vivo ◽  
Simultaneous Recording ◽  
Left Ventricular ◽  
Homogeneous Distribution ◽  
Large Animal ◽  
Electrical Pacing

To provide a model close to the human heart, and to study intrinsic cardiac function at the same time as electromechanical coupling, we developed a magnetic resonance (MR)-compatible setup of isolated working perfused pig hearts. Hearts from pigs (40 kg, n = 20) and sheep ( n = 1) were blood perfused ex vivo in the working mode with and without loaded right ventricle (RV), for 80 min. Cardiac function was assessed by measuring left intraventricular pressure and left ventricular (LV) ejection fraction (LVEF), aortic and mitral valve dynamics, and native T1 mapping with MR imaging (1.5 Tesla). Potential myocardial alterations were assessed at the end of ex vivo perfusion from late-Gadolinium enhancement T1 mapping. The ex vivo cardiac function was stable across the 80 min of perfusion. Aortic flow and LV-dP/d tmin were significantly higher ( P < 0.05) in hearts perfused with loaded RV, without differences for heart rate, maximal and minimal LV pressure, LV-dP/d tmax, LVEF, and kinetics of aortic and mitral valves. T1 mapping analysis showed a spatially homogeneous distribution over the LV. Simultaneous recording of hemodynamics, LVEF, and local cardiac electrophysiological signals were then successfully performed at baseline and during electrical pacing protocols without inducing alteration of MR images. Finally, 31P nuclear MR spectroscopy (9.4 T) was also performed in two pig hearts, showing phosphocreatine-to-ATP ratio in accordance with data previously reported in vivo. We demonstrate the feasibility to perfuse isolated pig hearts in the working mode, inside an MR environment, allowing simultaneous assessment of cardiac structure, mechanics, and electrophysiology, illustrating examples of potential applications.

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin

2014 ◽  
Vol 92 (5) ◽  
pp. 356-362 ◽  
Author(s):  
Traci L. Parry ◽  
David S. Hydock ◽  
Brock T. Jensen ◽  
Chia-Ying Lien ◽  
Carole M. Schneider ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Endurance Exercise ◽  
Cardiac Dysfunction ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Androgen Deprivation ◽  
Maximal Rate ◽  
Sprague Dawley ◽  
Developed Pressure

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague–Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)–1·d–1 by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (–21% and –27%), maximal rate of pressure development (–29% and –32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction

2007 ◽  
Vol 293 (4) ◽  
pp. H2418-H2428 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Anuradha Kalyanasundaram ◽  
Xue Zhao ◽  
Li Zuo ◽  
Poornima Bhupathy ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Salvage ◽  
Myocardial Infarct Size ◽  
Intracellular Ca ◽  
Developed Pressure

Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca2+ overload with reduced activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular Ca2+ homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster Ca2+ transport kinetics. Therefore, to further address this issue and to evaluate whether SERCA1a expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCA1a transgenic (SERCA1a+/+) and nontransgenic (NTG) mice. Langendorff-perfused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in SERCA1a+/+ mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, SERCA1a+/+ hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed better-preserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in SERCA1a+/+ hearts. Importantly, intraischemic Ca2+ levels were significantly lower in SERCA1a+/+ hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus SERCA1a+/+ hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic Ca2+ overload and thus provides potent myocardial protection.

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