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.

scholarly journals Studies to Elucidate the Mechanism of Cardio Protective and Hypotensive Activities of Anogeissus acuminata (Roxb. ex DC.) in Rodents

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3471
Author(s):  
Fatima Saqib ◽  
Muhammad Arif Aslam ◽  
Khizra Mujahid ◽  
Luigi Marceanu ◽  
Marius Moga ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Sprague Dawley ◽  
Positive Effects ◽  
Creatine Kinase Mb

Anogeissus acuminata (Roxb. ex DC.) is a folkloric medicinal plant in Asia; including Pakistan; used as a traditional remedy for cardiovascular disorders. This study was planned to establish a pharmacological basis for the trivial uses of Anogeissus acuminata in certain medical conditions related to cardiovascular systems and to explore the underlying mechanisms. Mechanistic studies suggested that crude extract of Anogeissus acuminata (Aa.Cr) produced in vitro cardio-relaxant and vasorelaxant effects in isolated paired atria and aorta coupled with in vivo decrease in blood pressure by invasive method; using pressure and force transducers connected to Power Lab Data Acquisition System. Moreover; Aa.Cr showed positive effects in left ventricular hypertrophy in Sprague Dawley rats observed hemodynamically by a decrease in cardiac cell size and fibrosis; along with absence of inflammatory cells; coupled with reduced levels of angiotensin converting enzyme (ACE) and renin concentration along with increased concentrations of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). In Acute Myocardial Infarction (AMI) model; creatine kinase (CK), creatine kinase-MB (CK-MB) and lactic acid dehydrogenase (LDH levels) were found to be decreased; along with decreased necrosis; edema and recruitment of inflammatory cells histologically. In vivo and ex vivo studies of Anogeissus acuminata provided evidence of vasorelaxant; hypotensive and cardioprotective properties facilitated through blockage of voltage-gated Ca++ ion channel; validating its use in cardiovascular diseases

scholarly journals Extracellular SPARC improves cardiomyocyte contraction during health and disease

2018 ◽  
Author(s):  
Sophie Deckx ◽  
Daniel M. Johnson ◽  
Marieke Rienks ◽  
Paolo Carai ◽  
Elza van Deel ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Matrix Protein ◽  
Contractile Function ◽  
Ex Vivo ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Coxsackie Virus ◽  
Extracellular Matrix Protein

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and in lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly improves cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury.

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.

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.

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.

scholarly journals Vascular KATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia

2020 ◽  
Vol 98 (8) ◽  
pp. 1149-1160
Author(s):  
Qadeer Aziz ◽  
Jianmin Chen ◽  
Amie J Moyes ◽  
Yiwen Li ◽  
Naomi A Anderson ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Ex Vivo ◽  
Critical Role ◽  
Lethal Dose ◽  
Systemic Infection ◽  
Cardiac Metabolism ◽  
Lipid Fatty Acid

Abstract KATP channels in the vasculature composed of Kir6.1 regulate vascular tone and may contribute to the pathogenesis of endotoxemia. We used mice with cell-specific deletion of Kir6.1 in smooth muscle (smKO) and endothelium (eKO) to investigate this question. We found that smKO mice had a significant survival disadvantage compared with their littermate controls when treated with a sub-lethal dose of lipopolysaccharide (LPS). All cohorts of mice became hypotensive following bacterial LPS administration; however, mean arterial pressure in WT mice recovered to normal levels, whereas smKO struggled to overcome LPS-induced hypotension. In vivo and ex vivo investigations revealed pronounced cardiac dysfunction in LPS-treated smKO, but not in eKO mice. Similar results were observed in a cecal slurry injection model. Metabolomic profiling of hearts revealed significantly reduced levels of metabolites involved in redox/energetics, TCA cycle, lipid/fatty acid and amino acid metabolism. Vascular smooth muscle-localised KATP channels have a critical role in the response to systemic infection by normalising cardiac function and haemodynamics through metabolic homeostasis. Key messages • Mice lacking vascular KATP channels are more susceptible to death from infection. • Absence of smooth muscle KATP channels depresses cardiac function during infection. • Cardiac dysfunction is accompanied by profound changes in cellular metabolites. • Findings from this study suggest a protective role for vascular KATP channels in response to systemic infection.

Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures

2006 ◽  
Vol 290 (4) ◽  
pp. H1699-H1705 ◽  
Author(s):  
K. A. Connelly ◽  
D. L. Prior ◽  
D. J. Kelly ◽  
M. P. Feneley ◽  
H. Krum ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Systolic Function ◽  
Normal Function ◽  
Left Ventricular ◽  
Doppler Imaging ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Loop Analysis ◽  
Shortening Velocity

Transgenic animal models have provided a vital insight into the pathogenesis of cardiovascular disease, but functional cardiac assessment is often limited by high heart rates and small heart size. We hypothesized that in the presence of concentric left ventricular (LV) hypertrophy (LVH), load-sensitive measures of contractility may be misinterpreted as overestimating global cardiac function, because the normal function of excess sarcomeres may displace a greater volume of blood during contraction. Conductance catheter technology was used to evaluate pressure-volume (P-V) relationships as a load-insensitive method of assessing cardiac function in vivo in 18-wk-old heterozygous (mRen-2)27 transgenic rats (a model of LVH), compared with age-matched Sprague-Dawley (SD) controls. Anesthetized animals underwent echocardiography followed by P-V loop analysis. Blood pressure, body weight, and heart rate were higher in the Ren-2 rats ( P < 0.05). Load-sensitive measures of systolic function, including fractional area change, fractional shortening, ejection fraction, and positive peak rate of LV pressure development, were greater in the Ren-2 than control animals ( P < 0.05). Load-insensitive measures of systolic function, including the preload recruitable stroke work relationship and the end-systolic P-V relationship, were not different between Ren-2 and SD rats. Regional wall motion assessed by circumferential shortening velocity suggested enhanced circumferential fiber contractility in the Ren-2 rats ( P = 0.02), but tissue Doppler imaging, used to assess longitudinal function, was not different between groups. Although conventional measures suggested enhanced systolic function in the Ren-2 rat, load-insensitive measures of contractility were not different between Ren-2 and SD animals. These findings suggest that the normal range of values for load-sensitive indexes of contractility needs to be altered according to the degree of LVH. To accurately identify changes in systolic function, we suggest that a combination of echocardiography with assessment of load-insensitive measures be used routinely.

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