Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Tanaka ◽  
T Nagoshi ◽  
A Yoshii ◽  
Y Oi ◽  
H Takahashi ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Cardiac Tissue ◽  
Left Ventricular ◽  
Purine Metabolism ◽  
Negative Regulator ◽  
Lv Function ◽  
Funding Source ◽  
Metabolic Reaction ◽  
Lv Dysfunction ◽  
Doxorubicin Administration

Abstract Background Accumulating evidence suggests that high serum uric acid (UA) is associated with left ventricular (LV) dysfunction. Although xanthine oxidase (XO) activation is a critical regulatory mechanism of the terminal step in ATP and purine degradation, the pathophysiological role of cardiac tissue XO in LV dysfunction remains unclear. Objectives We hypothesized that cardiac XO is activated in doxorubicin-induced LV dysfunction, and XO inhibitors ameliorate LV function by inhibiting cell death signals as well as by modifying cardiac purine metabolism. Methods Either doxorubicin (10 mg/kg) or vehicle was intraperitonially administered in a single injection to ICR mice. Mice were treated with or without oral XO inhibitors (febuxostat 3 mg/kg/day or topiroxostat 5 mg/kg/day) for 8 days starting 24 hours before doxorubicin-injection. The LV function was assessed by echocardiography at day 6 and by ex vivo heart perfusion at day 7. Results Cardiac tissue XO activity measured by a highly sensitive assay with liquid chromatography/mass spectrometry (n=8 each) and cardiac UA content (n=3–6) were significantly increased in doxorubicin-treated mice at day 7 and dramatically reduced by XO inhibitors. Accordingly, XO inhibitors substantially improved LV ejection fraction (n=8 each) and LV developed pressure (n=9 each) that had been impaired by doxorubicin administration. Intriguingly, the expression of GPX4, a negative regulator of ferroptosis, was decreased in doxorubicin-treated hearts but improved by XO inhibitors (n=6 each). Furthermore, metabolome analyses revealed an enhanced purine metabolism in doxorubicin-treated hearts, and XO inhibitors suppressed the serial metabolic reaction of hypoxanthine–xanthine–UA. Conclusions Doxorubicin administration induces cardiac tissue XO activation associated with an impaired LV function. XO inhibition attenuates the doxorubicin-induced cardiotoxicity partly through an anti-ferroptotic effect and the conservation of tissue ATP levels by modulating purine metabolism. The present study suggests that pharmacological XO inhibition represents a potential therapeutic strategy for the treatment of doxorubicin-induced cardiotoxicity. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported in part by grants-in-aid for Ministry of Education Culture, Sports, Science and Technology.

scholarly journals Heart failure in survivors of out-of-hospital cardiac arrest – factors associated with reduced systolic ventricular function at follow-up

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H.S.Z Bahrami ◽  
J Kjaergaard ◽  
J.H Thomsen ◽  
F Lippert ◽  
L Koeber ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Arrest ◽  
Hospital Discharge ◽  
Left Ventricular ◽  
Lv Function ◽  
Funding Source ◽  
Factors Associated ◽  
Lv Dysfunction ◽  
Hospital Cardiac Arrest

Abstract Background Survival after out-of-hospital cardiac arrest (OHCA) has increased in recent years but is still only 10%. Little is known about the association between post-resuscitation comorbidity and heart failure after discharge from the initial OHCA-admission. Purpose In OHCA-survivors we aimed to describe predictors of left ventricular (LV) dysfunction, defined as LV ejection fraction (LVEF) <40%, at follow-up. Methods A consecutive cohort of OHCA-patients with cardiac cause from 2007 to 2011 without a pre-OHCA congestive heart failure diagnosis (according to the Danish National Patient Registry, which holds data on all Danish citizens) were retrospectively examined. Logistic regression analyses were used to assess factors associated with LV dysfunction (LVEF <40%) at follow-up after a median of 6 months. Follow-up was not performed systematically in the OHCA-survivors and data from follow-up was assessed by reading of patient charts. Results A total of 365 OHCA-survivors with a mean age of 61 years were discharged alive from hospital. LVEF <40% at hospital discharge was seen in 54% (n=184, 7% missing), and at follow-up after a median of 6 months 19% (n=69) of the total OHCA-cohort of survivors still had LV dysfunction. Factors associated with LV dysfunction at follow-up were chronic ischemic heart disease (IHD) prior to OHCA (odds ratio (OR) = 2.9 (95% CI: 1.2 – 7.1)) and ST-elevation myocardial infarction (STEMI) as cause of OHCA (OR = 2.9 (1.4–6.0)), whereas age, gender, high comorbidity burden prior to OHCA or pre-hospital circumstances (including shockable cardiac arrest rhythm) were not. Conclusion More than half of OHCA-survivors with LVEF <40% at hospital discharge improved LV function and LV dysfunction at follow-up after a median of 6 months after discharge was present in 1 in 5 (19%) of the cohort. Chronic IHD and STEMI were the only factors significantly associated with LV dysfunction at follow-up. A systematic follow-up including echocardiography in the outpatient clinic for OHCA-survivors is recommended especially in patients with reduced LV function at discharge and in STEMI-patients in order to assess the appropriateness of heart failure medication and an implantable cardiac defibrillator. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Danish Foundation Trygfonden

scholarly journals Necroptosis inhibitor directly reduced left ventricular dysfunction in obese-insulin resistant rats, independent of the metabolic status

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Apaijai ◽  
K Jinawong ◽  
K Singhanat ◽  
T Jaiwongkam ◽  
S Kerdphoo ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Left Ventricular ◽  
Metabolic Parameters ◽  
Lv Function ◽  
Cardiac Diseases ◽  
Funding Source ◽  
Insulin Resistant ◽  
Lv Dysfunction

Abstract Background The number of obese people is increasing globally. Our previous studies showed that chronic high-fat diet (HFD) consumption led to obesity with peripheral insulin resistance, which was associated with left ventricular (LV) dysfunction. Mechanistically, cardiac mitochondrial dysfunction and cell death are proposed as an underlying mechanism for LV dysfunction in obese subjects. Recently, necroptosis was defined as a novel cell death pathway, which can be found in various types of cardiac diseases such as myocardial ischaemia and heart failure. Pharmacological inhibition of necroptosis by necrostatin 1 (nec-1) provided the favorable outcomes to those cardiac diseases. However, the roles of necroptosis and the effects of nec-1 on the heart of obese-insulin resistant rats have never been investigated. Purpose We hypothesized that nec-1 attenuates LV dysfunction by reducing cardiac mitochondrial dysfunction, necroptosis, and apoptosis in obese-insulin resistant rats. Methods Male rats (n=32) were fed with normal diet (ND) or HFD for 12 weeks to induce obese-insulin resistance. At weeks 13, HFD-fed rats were assigned into 3 interventional groups (n=8/group) as follows: 1) HFD-fed rats treated with saline, 2) HFD-fed rats treated with nec-1 (1.65 mg/kg/day, subcutaneous injection), 3) HFD-fed rats treated with metformin (300 mg/kg/day, oral gavage feeding, served as a positive control). ND rats were treated with saline. Rats received their assigned interventions for additional 7 weeks. Blood pressure (BP), cardiac sympathovagal balance, and LV function were determined. At the end, the heart was excised to determine cardiac mitochondrial function including mitochondrial respiration, reactive oxygen species (ROS) levels, membrane potential changes, swelling, as well as apoptosis and necroptosis protein levels. Results HFD-fed rats had increased body weight, visceral fat deposition, hyperinsulinemia with euglycemia, and dyslipidemia. Moreover, HFD-fed rats had increased systolic and diastolic BP, reduced cardiac sympathovagal balance, and %LV ejection fraction (LVEF) (Fig. 1A). For mitochondrial function, respiratory control ratio was decreased, ROS levels were increased, along with mitochondrial membrane depolarization and swelling (Fig. 1B). Both necroptosis and apoptosis were observed in HFD-fed rats. Treatment with nec-1 reduced systolic and diastolic BP, cardiac sympathovagal imbalance, and increased %LVEF (Fig. 1A). Necroptosis and apoptosis were reduced, and all mitochondrial function parameters were improved in nec-1 treated rats (Fig. 1B). However, the metabolic parameters were not modified by nec-1. Treatment with metformin had similar benefits as nec-1 (Fig. 1), with additional improvement in metabolic parameters in HFD-fed rats. Conclusion Nec-1 directly improves LV function in obese-insulin resistant rats via attenuating cardiac mitochondrial dysfunction and cell death, independent of metabolic parameters. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency, Thailand Research Fund (TRF)

Urine Albumin to Creatinine Ratio and Echocardiographic Left Ventricular Structure and Function in Patients with Essential Hypertension

2011 ◽  
Vol 9 (2) ◽  
pp. 90 ◽  
Author(s):  
Rohola Hemmati ◽  
Mojgan Gharipour ◽  
Hasan Shemirani ◽  
Alireza Khosravi ◽  
Elham Khosravi ◽  
...  
Keyword(s):  
Essential Hypertension ◽  
Peak Velocity ◽  
Left Ventricular ◽  
Lv Function ◽  
Creatinine Ratio ◽  
Uncomplicated Hypertension ◽  
Urine Albumin ◽  
Lv Dysfunction ◽  
Mitral Annulus Velocity ◽  
Lv Mass

Background:Appearance of microalbuminuria, particularly in patients with hypertension, might be associated with a higher prevalence of left ventricular (LV) dysfunction and geometric abnormalities. This study was undertaken to determine whether high urine albumin to creatinine ratio (UACR) as a sensitive marker for microalbuminuria can be associated with LV hypertrophy (LVH) and systolic and diastolic LV dysfunction.Methods:The study population consisted of 125 consecutive patients with essential uncomplicated hypertension. Urine albumin and creatinine concentration was determined by standard methods. LVH was defined as a LV mass index >100 g/m2 of body surface area in women and >130 g/m2 in men. Echocardiographic LV systolic and diastolic parameters were measured.Results:The prevalence of microalbuminuria in patients with essential hypertension was 5.6 %. UACR was significantly no different in patients with LVH than in patients with normal LV geometry (21.26 ± 31.55 versus 17.80 ± 24.52 mg/mmol). No significant correlation was found between UACR measurement and systolic and diastolic function parameters, including early to late diastolic peak velocity (E/A) ratio (R=-0.192, p=0.038), early diastolic peak velocity to early mitral annulus velocity (E/E') ratio (R=-0.025, p=0.794), LV ejection fraction (R=0.008, p=0.929), and LV mass (R=-0.132, p=0.154). According to the receiver operator characteristic (ROC) curve analysis, UACR measurement was not an acceptable indicator of LVH with areas under the ROC curves 0.514 (95 % confidence interval 0.394–0.634). The optimal cut-off value for UACR for predicting LVH was identified at 9.4, yielding a sensitivity of 51.6 % and a specificity of 48.3 %.Conclusion:In patients with uncomplicated essential hypertension, abnormal systolic and diastolic LV function and geometry cannot be effectively predicted by the appearance of microalbuminuria.

scholarly journals Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001614
Author(s):  
Mohammad R Ostovaneh ◽  
Raj R Makkar ◽  
Bharath Ambale-Venkatesh ◽  
Deborah Ascheim ◽  
Tarun Chakravarty ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Myocardial Function ◽  
Randomised Clinical Trial ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Lv Dysfunction ◽  
Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

scholarly journals Evolution of left ventricular function after Wharton's jelly mesenchymal stem cells transcoronary administration: 5-year follow up in a pilot cohort of CIRCULATE-AMI Randomized Trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Kwiecien ◽  
L Drabik ◽  
A Mazurek ◽  
M Sikorska ◽  
L Czyz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Infarct Size ◽  
Troponin T ◽  
Left Ventricular ◽  
Lv Function ◽  
Funding Source ◽  
Double Blind ◽  
Wharton's Jelly

Abstract Introduction CIRCULATE-Acute Myocardial Infarction is a double-blind controlled trial randomizing (RCT) in 105 consecutive patients with their first, large AMI (cMRI-LVEF ≤45% and/or cMRI-infarct size ≥10% of LV) with successful infarct-related artery (IRA) primary percutaneous coronary intervention (pPCI) to transcoronary administration of Wharton's Jelly Mesenchymal Stem Cells (WJMSCs) vs. placebo (2:1). The pilot study cohort (PSC) preceded the RCT. Aim To evaluate WJMSCs long-term safety, and evolution of left-ventricular (LV) function in CIRCULATE-AMI PSC. Material and methods 30 000 000 WJMSCs (50% labelled with 99mTc-exametazime) were administered via IRA in a ten-patient PCS (age 32–65 years, peak hs-Troponin T 17.3±9.1ng/mL and peak CK-MB 533±89U/L, cMRI-LVEF 40.3±2.7% and infarct size 20.1±2.8%) at ≈5–7 days after AMI using a cell delivery-dedicated, coronary-non-occlusive method. Other treatments were per guidelines. WJMSCs showed an unprecedented high myocardial uptake (30.2±5.3%; 95% CI 26.9–33.5%), corresponding to ≈9×10 000 000 cells retention in the infarct zone – in absence of epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45±8 vs. 44±9, p=0.51) or any hs-Troponin T elevation. Five-year follow up included cardiac Magnetic Resonance Imaging (cMRI) (at baseline, 1 year and 3 years) and detailed echocardiography (echo) at baseline, 1 year, 3 years and 5 years. Results By 5 years, one patient died from a new, non-index territory AMI. There were no other cardiovascular events and MACCE that might be related to WJMSCs transplantation. On echo (Fig), there was an increase in left ventricular ejection fraction (LVEF) between WJMSCs administration point and 1 year (37.7±2.9% vs. 48.3±2.5%, p=0.002) that was sustained at 3 years (47.2±2.6%, p=0.005 vs. baseline) and at 5 years: (44.7±3.2%, p=0.039 vs. baseline). LVEF reached a peak at 1 year after the AMI and WJMSCs transfer (Fig). cMRI data (obtained up to 3 years; 1 year 41.9±2.6% vs. 51.0±3.3%, p&lt;0.01; 3 years 52.2±4.0%, p&lt;0.01 vs. baseline) were consistent with the echo LVEF assessment. Conclusions 5-year follow up in CIRCULATE-AMI PSC indicates that WJMSC transcoronary application is safe and may be associated with an LVEF improvement. The magnitude of LV increase appears to peak at 1 year, suggesting a potential role for repeated WJMSCs administration(s). Currently running double-blind RCT will provide placebo-controlled insights into the WJMSCs effect(s) on changes in LV function, remodelling, scar reduction and clinical outcomes. Echo-LVEF evolution Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College

scholarly journals Uric Acid, Oxidative Stress and Inflammation in Chronic Heart Failure with Reduced Ejection Fraction

2015 ◽  
Vol 23 (4) ◽  
pp. 397-406 ◽  
Author(s):  
Adriana Iliesiu ◽  
Alexandru Campeanu ◽  
Daciana Marta ◽  
Irina Parvu ◽  
Gabriela Gheorghe
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Uric Acid ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Xanthine Oxidase ◽  
Left Ventricular ◽  
Paraoxonase 1 ◽  
Lv Function ◽  
The Relationship

Abstract Background. Oxidative stress (OS) and inflammation are major mechanisms involved in the progression of chronic heart failure (CHF). Serum uric acid (sUA) is related to CHF severity and could represent a marker of xanthine-oxidase activation. The relationship between sUA, oxidative stress (OS) and inflammation markers was assessed in patients with moderate-severe CHF and reduced left ventricular (LV) ejection fraction (EF). Methods. In 57 patients with stable CHF, functional NYHA class III, with EF<40%, the LV function was assessed by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels and echocardiographically through the EF and E/e’ ratio, a marker of LV filling pressures. The relationship between LV function, sUA, malondialdehyde (MDA), myeloperoxidase (MPO), paraoxonase 1 (PON-1) as OS markers and high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) as markers of systemic inflammation was evaluated. Results. The mean sUA level was 7.9 ± 2.2 mg/dl, and 61% of the CHF patients had hyperuricemia. CHF patients with elevated LV filling pressures (E/e’ ≥ 13) had higher sUA (8.6 ± 2.3 vs. 7.3 ± 1.4, p=0.08) and NT-proBNP levels (643±430 vs. 2531±709, p=0.003) and lower EF (29.8 ± 3.9 % vs. 36.3 ± 4.4 %, p=0.001). There was a significant correlation between sUA and IL-6 (r = 0.56, p<0.001), MDA (r= 0.49, p= 0.001), MPO (r=0.34, p=0.001) and PON-1 levels (r= −0.39, p= 0.003). Conclusion. In CHF, hyperuricemia is associated with disease severity. High sUA levels in CHF with normal renal function may reflect increased xanthine-oxidase activity linked with chronic inflammatory response.

Regulation of components of the brain and cardiac renin-angiotensin systems by 17β-estradiol after myocardial infarction in female rats

2006 ◽  
Vol 291 (1) ◽  
pp. R155-R162 ◽  
Author(s):  
Stephanie A. Dean ◽  
Junhui Tan ◽  
Roselyn White ◽  
Edward R. O’Brien ◽  
Frans H. H. Leenen
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Female Rats ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Brain Nuclei ◽  
Renin Angiotensin ◽  
Lv Dysfunction ◽  
17Β Estradiol ◽  
The Brain

The present study tested the hypothesis that 17β-estradiol (E2) inhibits increases in angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT1R) in the brain and heart after myocardial infarction (MI) and, thereby, inhibits development of left ventricular (LV) dysfunction after MI. Age-matched female Wistar rats were treated as follows: 1) no surgery (ovary intact), 2) ovariectomy + subcutaneous vehicle treatment (OVX + Veh), or 3) OVX + subcutaneous administration of a high dose of E2 (OVX + high-E2). After 2 wk, rats were randomly assigned to coronary artery ligation (MI) and sham operation groups and studied after 3 wk. E2 status did not affect LV function in sham rats. At 2–3 wk after MI, impairment of LV function was similar across MI groups, as measured by echocardiography and direct LV catheterization. LV ACE mRNA abundance and activity were increased severalfold in all MI groups compared with respective sham animals and to similar levels across MI groups. In most brain nuclei, ACE and AT1R densities increased after MI. Unexpectedly, compared with the respective sham groups the relative increase was clearest (20–40%) in OVX + high-E2 MI rats, somewhat less (10–15%) in ovary-intact MI rats, and least (<10–15%) in OVX + Veh MI rats. However, because in the sham group brain ACE and AT1R densities increased in the OVX + Veh rats and decreased in the OVX + high-E2 rats compared with the ovary-intact rats, actual ACE and AT1R densities in most brain nuclei were modestly higher (<20%) in OVX + Veh MI rats than in the other two MI groups. Thus E2 does not inhibit upregulation of ACE in the LV after MI and amplifies the percent increases in ACE and AT1R densities in brain nuclei after MI, despite E2-induced downregulation in sham rats. Consistent with these minor variations in the tissue renin-angiotensin system, during the initial post-MI phase, E2 appears not to enhance or hinder the development of LV dysfunction.

Impact of Valve Surgery on Serum Osteopontin Levels in Patients with Mitral Regurgitation

Cardiology ◽  
2015 ◽  
Vol 130 (2) ◽  
pp. 82-86
Author(s):  
H.M. Gunes ◽  
G.B. Guler ◽  
E. Guler ◽  
G.G. Demir ◽  
S. Hatipoglu ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Left Ventricular ◽  
Valve Surgery ◽  
Lv Function ◽  
Vena Contracta ◽  
Atherosclerotic Lesions ◽  
Lv Dysfunction ◽  
Echocardiographic Parameters ◽  
Artery Disease ◽  
The Impact

Objective: Osteopontin (OPN), a sialoprotein present within atherosclerotic lesions, especially in calcified plaques, is linked to the progression of coronary artery disease and heart failure. We assessed the impact of valve surgery on serum OPN and left ventricular (LV) function in patients with mitral regurgitation (MR). Methods: Thirty-two patients with severe MR scheduled for surgery were included in the study. Echocardiography markers were assessed preoperatively and at 3 months following the surgery and matched with the serum OPN levels. Results: Valve surgery was associated with a reduction of the ejection fraction (EF) from 55.2 ± 6.3 to 48.8 ± 7.1% after surgery, p < 0.001. Following surgery, the OPN level was significantly higher than preoperatively (mean 245, range 36-2,284 ng/ml vs. 76, 6-486 ng/ml, p = 0.007). Preoperative OPN exhibited a slight negative correlation with the EF (r = -0.35, p = 0.04), and a moderate correlation with vena contracta (r = -0.38, p = 0.02). There were no other meaningful correlations between conventional echocardiographic parameters and OPN. Conclusion: Following valve surgery due to severe MR, patients exhibited a decrease in EF and an increase in OPN levels. The assessment of preoperative OPN failed to strongly predict probable LV dysfunction.

Abstract 14119: Contrasting Effects of Exercise Training After Acute Myocardial Infarction versus Aortic Stenosis Depend Critically on the Regulation of Endothelial Nitric Oxide Synthase

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yanti Octavia ◽  
Elza D van Deel ◽  
Monique de Waard ◽  
Martine de Boer ◽  
Dirk J Duncker
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Exercise Training ◽  
Wheel Running ◽  
Left Ventricular ◽  
Lv Function ◽  
Enhanced Chemiluminescence ◽  
Lv Dysfunction ◽  
Enos Uncoupling ◽  
Endothelial Nitric Oxide

Introduction: The cardiovascular benefits of exercise training (EX) are widely appreciated. Previously we found that the cardiac effects of EX critically depend on the underlying cause of heart disease. Hypothesis: The underlying etiology determines how EX affects the endothelial nitric oxide (NO) synthase (eNOS)-mediated balance between NO and superoxide (O2-). Methods: Mice were subjected to sham surgery, myocardial infarction (MI) or transverse aortic constriction (TAC), and subsequently exposed to 8 weeks of voluntary wheel running or sedentary housing. Left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements; fibrosis by Picro-sirius Red staining; peroxynitrite (ONOO-) and O2- production by luminol- and lucigenin-enhanced chemiluminescence respectively, with or without the NOS inhibitor L-NAME; eNOS uncoupling and eNOS S-glutathionylation by western blot and coimmunoprecipitation, respectively; cardiac NO by the Griess reaction. Results: EX ameliorated LV dysfunction and fibrosis in MI but not TAC (Table 1). Strikingly, O2- generation was blunted by EX in MI, but exacerbated by EX in TAC, which was largely NOS-dependent. Accordingly, eNOS uncoupling and eNOS S-glutathionylation were corrected by EX in MI but aggravated in TAC mice. In parallel, ONOO- levels was attenuated by EX in MI but aggravated by EX in TAC. Cardiac NO levels were reduced in MI and TAC and normalized by EX in MI. Conclusions: The contrasting effects of EX in MI vs TAC can be explained by the highly divergent effects of EX on eNOS regulation, resulting in blunted vs aggravated oxidative stress by EX in MI vs TAC.

Abstract 3474: Cardiac -Specific SOCS3 Dificient Mice Shows Resistance to Lipopolysaccharide-Induced Cardiac Dysfunction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Futamata Nobuyoshi ◽  
Hldeo Yasukawa ◽  
Toyoharu Ohba ◽  
Kazutoshi Mawatari ◽  
Daisuke Fukui ◽  
...  
Keyword(s):  
Western Blot ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Left Ventricular Ejection ◽  
Cytokine Signaling ◽  
Rt Pcr ◽  
Lv Dysfunction ◽  
Stat3 Signaling ◽  
Cardiomyocyte Survival

Background : Lypopolysaccharide (LPS)-induced left ventricular (LV) dysfunction is a well-established model for sepsis-induced acute heart failure. STAT3 signaling in the heart has been shown to promote cardiomyocyte survival during LPS-induced LV dysfunction. Little is known, however, about the role of negative regulation of STAT3 signaling during LPS-induced LV dysfunction. Suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of gp130 cytokine-induced STAT3 signaling that plays an important role in cardiomyocyte survival. In this study, we determined whether STAT3 signaling and its negative regulator SOCS3 would play a role in LPS-induced LV dysfunction. Methods and Results : We examined the activation of STAT3 and inductions of gp130 cytokines and SOCS3 in the wild-type (WT) mice hearts after LPS injection by western blot and real-time PCR (RT-PCR). RT-PCR revealed that gp130 cytokines were markedly increased after AMI. Western blot revealed that STAT3 was markedly phosphorylated and SOCS3 was induced in WT mice hearts after LPS injection. To investigate the role of STAT3 signaling and SOCS3 in LPS-induced LV dysfunction, we generated cardiac-specific SOCS3 knockout mice (SOCS3-CKO). Left ventricular ejection fraction (LVEF) of SOCS3-CKO mice was similar to that of WT mice at baseline (64.2 ± 6.1 vs. 62.4 ± 4.4%). LPS (30mg/kg) elicited a significant and robust reduction of LVEF in both SOCS3-CKO mice and WT mice 3 hr after LPS injection (18 ± 4.5 vs. 16 ± 5.2%, p <0.01). LVEF in WT mice was further reduced 6 hr after LPS injection. On the other hand, interestingly, LVEF was restored to the baseline in SOCS3-CKO mice 6 hr after LPS injection (10.4 ± 3.9 vs. 62.2 ± 8.1%, p <0.01). Also the duration and intensity of STAT3 phosphorylation after LPS injection was greater in SOCS3-CKO mice than WT mice. Furthermore, SOCS3-CKO mice showed greater survival rate than WT mice after LPS injection ( p <0.01). Conclusion : Our data show that the deletion of SOCS3 in cardiomyocytes prevents the LPS-induced LV dysfunction in mice, possibly by augmenting the STAT3-mediated gp130 cytokine signaling.

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