Abstract 276: The Regulatory Effects Of Peroxiredoxin II On Phospholamban Phosphorylation And Cardiac Contractile Function In Vivo

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Wen Zhao ◽  
Xiaojing Shi ◽  
Wenjuan Zhou ◽  
Huimin Wang ◽  
Xuepeng Geng ◽  
...  
Keyword(s):  
Cardiac Contractility ◽  
Left Ventricular ◽  
Active Inhibitor ◽  
Rat Cardiomyocytes ◽  
Cardiac Contractile ◽  
Adenoviral Delivery ◽  
Anti Oxidant ◽  
Contraction And Relaxation ◽  
Phospholamban Phosphorylation

Peroxiredoxin II (prxII), a cytosolic form of the anti-oxidant peroxiredoxin family, was recently found to be decreased in failing human hearts. Interestingly, in hyperdynamic hearts of two genetically modified mouse models with: a) phospholamban ablation; and b) overexpression of the active inhibitor-1 of protein phosphatase 1, the levels of this cellular peroxidase (prxII) were markedly increased. Acute overexpression of prxII by adenoviral-delivery in adult rat cardiomyocytes (Ad-prxII) was associated with decreases in the basal rates of contraction and relaxation, as well as calcium kinetics. Accordingly, Ad-prxII-AS infected cardiomyocytes exhibited enhanced contractile parameters and Ca-kinetics. The depressed or increased contractility by Ad-prxII or Ad-prxII-AS was associated with parallel decreases or increases in phosphorylation of phospholamban (Ser16 and Thr17). To determine the in vivo effects of prxII on cardiac contractility, three transgenic lines (TG) with 2-3 fold cardiac-specific overexpression of prxII were generated and their cardiac morphologic and functional phenotypes were characterized. The TG mice exhibited no alterations in cardiac pathology or morphology up to 4 months of age. However, langendorf perfusions revealed that cardiac contractility, including the rates of contraction and relaxation (±dp/dtmax) as well as the left ventricular end systolic pressure (LVESP), were significantly depressed in TG mice (to 75, 76 and 63%, respectively), compared to WTs (100%). The depressed function was not associated with any alterations in the expression levels of key SR calcium handling proteins: SERCA2, total phospholamban, calsequestrin and ryanodine receptor. However, the levels of the phosphorylated PLN at Ser16 were found to be reduced to 50% in the TG mice, compared to WTs. These findings indicate that prxII, an anti-oxidant protein, may regulate basal cardiac contractile performance in vivo through phospholamban phosphorylation.

Abstract 419: Stim1 is Associated With Calcium Microdomains That are Required for Myofilament Remodeling and Signaling During Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Cory Parks ◽  
Ryan D Sullivan ◽  
Salvatore Mancarella
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Excitable Cells ◽  
Rat Cardiomyocytes ◽  
Cell Contractility

Stromal Interaction Protein 1 (STIM1) is the intracellular component of the store operated calcium channels. It is a ubiquitous Ca2+ sensor, prevalently located in the sarcoplasmic reticulum. In non-excitable cells, STIM1 is a key element in the generation of Ca2+signals that lead to gene expression and cell proliferation. A growing body of literature now suggests that STIM1 is important for normal heart function and plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM1 and the Ca2+ signaling in excitable cells are not clearly established. We show that in neonatal rat cardiomyocytes, the spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilaments remodeling and spatially segregated activation of pro-hypertrophic factors. Indeed, in vivo data obtained from an inducible cardiac restricted STIM1 knockout mouse, exhibited left ventricular dilatation associated with reduced cardiac contractility, which was corroborated by impaired single cell contractility. Furthermore, mice lacking STIM1 showed less adverse structural remodeling in response to pathological pressure overload-induced cardiac hypertrophy (transverse aortic constriction, TAC). We further show that the Ca2+ pool associated with STIM1 is the ON switch for extracellular signal-regulated kinase (ERK1/2)-mediated cytoplasm to nucleus signaling. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling, signaling and cardiac function, even when excitation-contraction coupling is present.

Effect of human urotensin-II infusion on hemodynamics and cardiac function

2003 ◽  
Vol 81 (2) ◽  
pp. 125-128 ◽  
Author(s):  
Ghada S Hassan ◽  
Fazila Chouiali ◽  
Takayuki Saito ◽  
Fu Hu ◽  
Stephen A Douglas ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Urotensin Ii ◽  
Ventricular Systolic Pressure ◽  
Wide Range ◽  
Dose Dependent Decrease

Recent studies have shown that the vasoactive peptide urotensin-II (U-II) exerts a wide range of action on the cardiovascular system of various species. In the present study, we determined the in vivo effects of U-II on basal hemodynamics and cardiac function in the anesthetized intact rat. Intravenous bolus injection of human U-II resulted in a dose-dependent decrease in mean arterial pressure and left ventricular systolic pressure. Cardiac contractility represented by ±dP/dt was decreased after injection of U-II. However, there was no significant change in heart rate or diastolic pressure. The present study suggests that upregulation of myocardial U-II may contribute to impaired myocardial function in disease conditions such as congestive heart failure.Key words: urotensin-II, rat, infusion, heart.

scholarly journals Positive impact of cardiac contractile modulation on myocardial contractility and left ventricular synchronization in a patient with a left ventricular noncompaction

2020 ◽  
Vol 35 (2) ◽  
pp. 157-162
Author(s):  
I. A. Ryabov ◽  
I. N. Mamchur ◽  
T. Yu. Chichkova ◽  
S. E. Mamchur ◽  
I. N. Sizova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Contractility ◽  
Positive Impact ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cardiac Contractile ◽  
Heart Failure Questionnaire

The article provides a clinical case of a 58-year-old man with the fi rst clinical manifestation of chronic heart failure in the presence of a signifi cant decrease in the left ventricular ejection fraction. Left ventricular non-compaction cardiomyopathy was diagnosed by echocardiography. After 12 months, a cardiac contractility modulation device was implanted to the patient in the presence of disease progression despite optimal medical therapy. We assessed the course of disease, quality of life, exercise tolerance, and myocardial contractility of the patient before and six months after surgery. The methods of assessment were collection of patient complaints, physical examination, electrocardiography (ECG), fi lling out the Minnesota Living with Heart Failure Questionnaire (MLHFQ), sixminute walk test, spiroergometry, and echocardiography.

Abstract 165: The 18 kDa FGF-2 Prevents the Doxorubicin-induced Cardiac Damage and Amp-activated Kinase Activation, in vitro and in vivo

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Navid Koleini ◽  
Jon Jon Santiago ◽  
Barbara E Nickel ◽  
Robert Fandrich ◽  
Davinder S Jassal ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cell Death ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Wild Type ◽  
Rat Cardiomyocytes ◽  
Ventricular Ejection Fraction ◽  
Compound C

Introduction: Protection of the heart from chemotherapeutic (Doxorubicin, DOX) drug-induced toxicity is a desirable goal, to limit side effects of cancer treatments. DOX toxicity has been linked to the activation (phosphorylation) of the AMP-activated kinase, AMPK. The 18 kDa low molecular weight isoform of fibroblast growth factor 2 (Lo-FGF-2) is a known cardioprotective and cytoprotective agent. In this study we have tested the ability of Lo-FGF-2 to protect from DOX-induced damage in rat cardiomyocytes in vitro, and in transgenic mouse models in vivo, in relation to AMPK activation. Methods: Rat neonatal cardiomyocytes in culture were exposed to DOX (0.5 μM) in the presence or absence of pre-treatment Lo-FGF-2 (10 ng/ml). Compound C was used to block phosphorylation (activity) of AMPK. Levels of cell viability/death (using Calcein-AM/Propidium iodide assay), phospho -and total AMPK, and apoptotic markers such as active caspase 3 were analyzed. In addition, transgenic mice expressing only Lo-FGF2, and wild type mice, expressing both high molecular weight (Hi-FGF2) as well as Lo-FGF2 were subjected to DOX injection (20 mg/kg, intraperitoneal); echocardiography was used to examine cardiac function at baseline and at 10 days post-DOX. Results: DOX-induced cell death of cardiomyocytes in culture was maximal at 24 hours post-DOX coinciding with significantly increased in activated (phosphorylated) AMPK. Compound C attenuated DOX-induced cardiomyocyte loss. Pre-incubation with Lo-FGF-2 decreased DOX induced cell death, and also attenuated the phosphorylation of AMPK post-DOX. Relative levels of phospho-AMPK were lower in the hearts of Lo-FGF2-expressing male mice compared to wild type. DOX-induced loss of contractile function (left ventricular ejection fraction and endocardial velocity) was negligible in Lo-FGF2-expressing mice but significant in wild type mice. Conclusion: Lo-FGF-2 protects the heart from DOX-induced damage in vitro and in vivo, by a mechanism likely involving an attenuation of AMPK activity.

scholarly journals Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion

2014 ◽  
Vol 306 (7) ◽  
pp. H1066-H1077 ◽  
Author(s):  
JuFang Wang ◽  
Jianliang Song ◽  
Erhe Gao ◽  
Xue-Qian Zhang ◽  
Tongda Gu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Wild Type ◽  
Protein Levels ◽  
Plasmic Reticulum ◽  
Intracellular Ca ◽  
Similar Survival

Phospholemman (PLM), when phosphorylated at Ser68, inhibits cardiac Na+/Ca2+ exchanger 1 (NCX1) and relieves its inhibition on Na+-K+-ATPase. We have engineered mice in which expression of the phosphomimetic PLM S68E mutant was induced when dietary doxycycline was removed at 5 wk. At 8–10 wk, compared with noninduced or wild-type hearts, S68E expression in induced hearts was ∼35–75% that of endogenous PLM, but protein levels of sarco(endo)plasmic reticulum Ca2+-ATPase, α1- and α2-subunits of Na+-K+-ATPase, α1c-subunit of L-type Ca2+ channel, and phosphorylated ryanodine receptor were unchanged. The NCX1 protein level was increased by ∼47% but the NCX1 current was depressed by ∼34% in induced hearts. Isoproterenol had no effect on NCX1 currents but stimulated Na+-K+-ATPase currents equally in induced and noninduced myocytes. At baseline, systolic intracellular Ca2+ concentrations ([Ca2+]i), sarcoplasmic reticulum Ca2+ contents, and [Ca2+]i transient and contraction amplitudes were similar between induced and noninduced myocytes. Isoproterenol stimulation resulted in much higher systolic [Ca2+]i, sarcoplasmic reticulum Ca2+ content, and [Ca2+]i transient and contraction amplitudes in induced myocytes. Echocardiography and in vivo close-chest catheterization demonstrated similar baseline myocardial function, but isoproterenol induced a significantly higher +dP/d t in induced compared with noninduced hearts. In contrast to the 50% mortality observed in mice constitutively overexpressing the S68E mutant, induced mice had similar survival as wild-type and noninduced mice. After ischemia-reperfusion, despite similar areas at risk and left ventricular infarct sizes, induced mice had significantly higher +dP/d t and −dP/d t and lower perioperative mortality compared with noninduced mice. We propose that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease.

Abstract 3810: Antiviral RNA Interference Mediated by a Recombinant Cardiotropic AAV9 Vector Improves Cardiac Function in Coxsackievirus B3 Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wolfgang Poller ◽  
Isaac Sipo ◽  
Dirk Westermann ◽  
Jens Kurreck ◽  
Roland Vetter ◽  
...  
Keyword(s):  
Rna Interference ◽  
Coxsackievirus B3 ◽  
Left Ventricular ◽  
Lv Function ◽  
Target Cells ◽  
Small Interfering Rnas ◽  
Rat Cardiomyocytes ◽  
Terminal Heart Failure ◽  
Novel Therapeutic

RNA interference (RNAi) has potential to be a novel therapeutic strategy in diverse areas of medicine. We report here on targeted RNAi for the treatment of a viral cardiomyopathy which is a major cause of sudden cardiac death or terminal heart failure in children and young adults. RNAi therapy employs small regulatory RNAs to achieve its effect but in vivo use of synthetic small interfering RNAs is limited by instability in plasma and low transfer into target cells. We instead evaluated an RNAi strategy using short hairpin RNA (shRdRp) directed at the RNA polymerase (RdRP) of Coxsackievirus B3 (CoxB3) in HeLa cells, primary rat cardiomyocytes (PNCMs), and CoxB3-infected mice in vivo. A conventional AAV2 vector expressing shRdRp protected HeLa against virus-induced death, but this vector type was unable to transduce PNCMs. In contrast, an analogous pseudotyped AAV2.6 vector was protective also in PNCMs and reduced virus replication by >3 log10 steps. Finally, we evaluated intravenous treatment of mice with an AAV2.9-shRdRp vector since AAV9 carries the most cardiotropic AAV capsid currently known for in vivo use. Mice with CoxB3 cardiomyopathy had disturbed left ventricular (LV) function with impaired parameters of contractility (dP/dtmax 3006±287 vs. 7482±487 mmHg/s, p<0.01) and diastolic relaxation (dP/dtmin -2224±195 vs. -6456±356 mmHg/s, p<0.01 and Tau 16.2±1.1 vs. 10.7±0.6 ms, p<0.01) as compared to control mice. AAV2.9-shRdRp treatment significantly attenuated the cardiac dysfunction compared to control vector-treated mice on day 10 after CoxB3 infection: dP/dtmax 3865±354 vs. 3006±287 mmHg/s (p<0.05) and dP/dtmin -3245±231 vs. −2224±195, mmHg/s (p<0.05), and Tau 11.9±0.5 vs. 16.2±1.1 ms (p<0.01). The data show, for the first time, that intravenously injected AAV9 has the potential to target RNAi to the heart and suggest AAV9-shRNA vectors as a novel therapeutic approach for cardiac disorders.

scholarly journals Endocannabinoids acting at CB1receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats

2007 ◽  
Vol 293 (3) ◽  
pp. H1689-H1695 ◽  
Author(s):  
Sándor Bátkai ◽  
Partha Mukhopadhyay ◽  
Judith Harvey-White ◽  
Raouf Kechrid ◽  
Pál Pacher ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Liver Cirrhosis ◽  
Cardiac Contractility ◽  
Receptor Expression ◽  
Contractile Dysfunction ◽  
Cirrhotic Cardiomyopathy ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance, and cardiac dysfunction, termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB1receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB1receptors have also been implicated in the decreased β-adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development. Rats with CCl4-induced cirrhosis developed decreased cardiac contractility, as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure, and tachycardia. Bolus intravenous injection of the CB1antagonist AM251 (3 mg/kg) acutely increased mean blood pressure, as well as both load-dependent and -independent indexes of systolic function, whereas no such changes were elicited by AM251 in control rats. Furthermore, tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared with control rats, without any change in 2-arachidonoylglycerol levels, whereas, in the cirrhotic liver, both 2-arachidonoylglycerol (6-fold) and anandamide (3.5-fold) were markedly increased. CB1-receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB1receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB1-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.

scholarly journals Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice

2009 ◽  
Vol 296 (4) ◽  
pp. H1069-H1079 ◽  
Author(s):  
Halvor K. Mørk ◽  
Ivar Sjaastad ◽  
Ole M. Sejersted ◽  
William E. Louch
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Shortening Velocity ◽  
Transient Time

Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca2+ homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals (∼2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 ± 0.1 vs. 1.9 ± 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca2+ transient time to peak values were prolonged in chronic CHF (115 ± 6 and 158 ± 11% sham values, respectively). Surprisingly, contraction and Ca2+ transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca2+ content and greater Ca2+ influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca2+ transients suggest that slowing of Ca2+ release is a critical mediator of CHF progression.

scholarly journals The Trend of β3-Adrenergic Receptor in the Development of Septic Myocardial Depression: A Lipopolysaccharide-Induced Rat Septic Shock Model

Cardiology ◽  
2018 ◽  
Vol 139 (4) ◽  
pp. 234-244 ◽  
Author(s):  
Ni Yang ◽  
Xiao-Lu  Shi ◽  
Bing-Lun  Zhang ◽  
Jian  Rong ◽  
Tie-Ning Zhang ◽  
...  
Keyword(s):  
Septic Shock ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Myocardial Depression ◽  
Rat Cardiomyocytes ◽  
Neonatal Cardiomyocytes ◽  
Nos Inhibitors ◽  
Lps Treatment

Septic shock with low cardiac output is very common in children. However, the mechanism underlying myocardial depression is unclear. The role of β3-AR in the development of myocardial depression in sepsis is unknown. In the present study, we generated an adolescent rat model of hypodynamic septic shock induced by lipopolysaccharide (LPS). Neonatal cardiomyocytes were also treated with LPS to mimic myocardial depression in sepsis, which was confirmed via an in vivo left ventricular hemodynamic study, and measurements of contractility and the Ca2+ transient in isolated adolescent and neonatal cardiomyocytes. After 16 h of LPS treatment, cultured neonatal cardiomyocytes showed a diminished Ca2+ transient amplitude associated with an increase in the β3-AR level. With the addition of a β3-AR agonist, the Ca2+ transient in LPS-treated neonatal rat cardiomyocytes gradually decreased over time; such a change was absent in cells treated with nitric oxide synthase (NOS) inhibitors prior to treatment with a β3-AR agonist. In adolescent rats with septic myocardial depression, cardiac function declined as indicated by decreased MAP, dP/dtmax, and dP/dtmix for 6 h after LPS injection; however, the β3-AR level first increased 2 h after LPS treatment and then decreased 6 h after LPS treatment in the absence of exogenous catecholamines. The results indicate that, in vitro, at the cellular level β3-AR may be involved in the development of myocardial depression (Ca2+ transient depression) in sepsis through NOS signaling pathways; however, in vivo, a complicated mechanism for modulating β3-AR may exist.

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