Abstract WMP77: SUMO1 Plays an Important Role in Cardiac Dysfunction After Intracerebral Hemorrhage in Aged Mice

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Wei Li ◽  
Michael Chopp ◽  
Poornima Venkat ◽  
Zhili Chen ◽  
Alex Zacharek ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Cardiac Dysfunction ◽  
Calcium Binding ◽  
Contractile Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
Ventricular Ejection Fraction ◽  
Aged Mice

Background: The conjugation of the small ubiquitin-like modifier1 (SUMO1) plays an important role in numerous biological processes, including DNA repair and signal transduction. SUMO1 also reduces cardiac oxidative stress and hypertrophy as well as induces neuroprotective effects. Intracerebral hemorrhage (ICH) induces cardiac deficit in the absence of primary cardiac diseases in young adult wild type mice. In this study, we tested the hypothesis that SUMO1 plays a key role in regulating brain-heart interaction after ICH, and SUMO1 deficit leads to worse brain and heart deficit after ICH in aged mice. Methods: Aged (16-20 months) female Sumo1-deficient (SUMO1-/-) mice or wild-type (SUMO1+/+) mice were subjected to ICH by injecting collagenase IV into the basal ganglia. Cardiac function was measured by echocardiography before ICH induction and at 7 days after ICH. Modified neurological severity (mNSS) ,foot-fault and adhesive removal tests were performed at 1, 3, 6 days after ICH to investigate neurological function. Cognitive functional tests (odor and novel objective tests) were performed before sacrificing the mice at 10 days after ICH, and then histological and immunohistochemically staining were used to evaluate the mechanisms. Results: Compared to SUMO1+/+ mice, SUMO1-/- mice did not exhibit significant cardiac deficit before ICH in aged mice. Compared to SUMO1+/+ICH mice, SUMO1-/-ICH mice exhibit significantly (p<0.05) increased: 1) brain hemorrhage volume and induced worse neurological and cognitive deficits, 2) cardiac dysfunction identified by decreased cardiac contractile function measured by left ventricular ejection fraction (LVEF) and fractional shortening (FS); 3) cardiac hypertrophy and fibrosis; 4) ionized calcium binding adaptor molecule (IBA1) positive macrophages/microglia and CD45 positive leukocyte infiltration into both heart and brain tissue. Conclusions: Aged SUMO1 deficient mice subjected to ICH not only exhibit increased neurological and cognitive functional deficit, but also significantly increased cardiac dysfunction and inflammatory cell infiltration into heart. These data suggest that SUMO1 plays an important role in brain-heart interaction and SUMO1 impacts brain-cardiac dysfunction after ICH.

Abstract 12624: Blockade of Exosome Secretion Attenuates Inflammatory Cytokines, Mitigates Cardiac Dysfunction, and Reduces Mortality in Polymicrobial Sepsis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xiaohong Wang ◽  
Dongze Qin ◽  
Kobina Essandoh ◽  
Wei Huang ◽  
Liwang Yang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Contractile Function ◽  
Cecal Ligation ◽  
Left Ventricular ◽  
Polymicrobial Sepsis ◽  
Raw 264.7 Cells ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Tnf Α

Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored. Methods and Results: C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p<0.01). Myocardial contractile function, assessed at 12h post-CLP using a SONOS-7500 echocardiography system, revealed that pre-injection of GW4869 significantly attenuated CLP-associated cardiac dysfunction, evidenced by an improved left ventricular ejection fraction (LVEF) and minor axis fractional shortening (LVFS), compared to DMSO controls (n=8-10, p<0.01). Myeloperoxidase (MPO) activity, a marker of myocardial inflammation, measured with a [[Unable to Display Character: &#64258;]]uorometric assay kit, also showed a significant reduction in GW4869-pre-treated mice, compared to DMSO-controls (n=5, p<0.01). Similarly, serum levels of inflammatory cytokines TNF-α and IL-1β triggered by CLP were reduced by 72% and 61%, respectively in GW4869-treated mice, compared with controls (n=6). Furthermore, we observed that 67% (n=9) of the DMSO controls, but only 20% in GW4869-treated mice (n=10) had died by 48h post-CLP. In vitro study confirmed that GW4869 limited the production of TNF-α and IL-1β in RAW 264.7 cells (a mouse macrophage cell line) challenged with endotoxin (LPS, 1μg/ml, 24 h). Conclusions: Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.

Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial

2007 ◽  
Vol 25 (25) ◽  
pp. 3859-3865 ◽  
Author(s):  
Thomas M. Suter ◽  
Marion Procter ◽  
Dirk J. van Veldhuisen ◽  
Michael Muscholl ◽  
Jonas Bergh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Adverse Effects ◽  
Cancer Patients ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Ventricular Ejection Fraction ◽  
Neo Adjuvant Chemotherapy

Purpose The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2–positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF ≥ 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. Results Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index. Conclusion Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

Abstract 137: Deficiency of Senescence Marker Protein 30 Exacerbates Doxorubicin-Induced Cardiac Dysfunction in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Makiko Miyata ◽  
Satoshi Suzuki ◽  
Tomofumi Misaka ◽  
Shu-ichi Saitoh ◽  
Yasuchika Takeishi
Keyword(s):  
Cardiac Dysfunction ◽  
Protective Role ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Marker Protein ◽  
Morphological Examination ◽  
Protective Function ◽  
Ventricular Ejection Fraction ◽  
Wide Range ◽  
Oxidative Effects

Background: Senescence marker protein 30 (SMP30) was originally identified as an aging marker protein in the rat liver. The expression of SMP30 decreases with aging androgen-independently. Doxorubicin (DOX) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. SMP30 may have anti-oxidative and anti-apoptosis functions in several organs, but functional role of SMP30 has not been rigorously examined in the heart. We hypothesized that SMP30 has cardio-protective function by anti-aging and anti-oxidant effects on DOX-induced cardiac dysfunction. Method and Results: Male SMP30 knockout (SMP30KO) and age-matched littermate male wild-type (WT) mice at 12-14 weeks of age were given intraperitoneal injections of DOX (20 mg/kg) or saline. Seven days after DOX injection, echocardiography revealed that left ventricular ejection fraction in DOX-treated SMP30KO mice was more severely reduced than in DOX-treated WT mice (40.9 ± 3.1% vs. 46.9 ± 4.9%, P<0.01). Morphological examination of myocardial sections showed fibrotic change in DOX-treated SMP30KO mice significantly increased compared to DOX-treated WT mice (3.2 ± 0.5% vs. 1.3 ± 0.2%, P<0.01). Generation of reactive oxygen species assessed by dihydroethidium staining was greater in DOX-treated SMP30KO mice than DOX-treated WT mice (166.9 ± 8.6% vs. 131.6 ± 5.8%, P<0.01). Moreover, apoptotic signaling pathways such as caspase-3 activity (1.8 ± 0.1% vs. 1.1 ± 0.2%, P<0.01), bax/bcl-2 ratio (2.4 ± 0.3% vs.1.6 ± 0.2%, P<0.05) and phosphorylation activity of c-Jun N-terminal kinase (1.6 ± 0.3 vs. 1.0 ± 0.1, P<0.05) were significantly elevated in the SMP30KO mice compared with WT mice after DOX injection. The numbers of TUNEL-positive nuclei in the myocardium were higher in DOX-treated SMPKO mice than in DOX-treated WT mice (0.15 ± 0.02% vs. 0.08 ± 0.01%, P<0.01). Conclusions: The results of this study demonstrated that DOX-induced cardiotoxicity is aggravated in SMP30KO mice by exacerbating of superoxide generation, leading to enhanced apoptosis of cardiomyocytes. SMP30 has a cardio-protective role by anti-apoptotic and anti-oxidative effects in DOX-induced cardiotoxicity.

Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation

2010 ◽  
Vol 28 (25) ◽  
pp. 3910-3916 ◽  
Author(s):  
Daniela Cardinale ◽  
Alessandro Colombo ◽  
Rosalba Torrisi ◽  
Maria T. Sandri ◽  
Maurizio Civelli ◽  
...  
Keyword(s):  
At Risk ◽  
Cardiac Dysfunction ◽  
Troponin I ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Trastuzumab Therapy ◽  
Before And After ◽  
Patients At Risk ◽  
Prognostic Implications

Purpose Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated. Patients and Methods In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%. Results TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio [HR], 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001). Conclusion TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

2018 ◽  
Vol 47 (5) ◽  
pp. 361-371 ◽  
Author(s):  
Qing Kuang ◽  
Ning Xue ◽  
Jing Chen ◽  
Ziyan Shen ◽  
Xiaomeng Cui ◽  
...  
Keyword(s):  
Renal Function ◽  
Hydrogen Sulfide ◽  
Cardiac Dysfunction ◽  
Mononuclear Cells ◽  
Troponin T ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H2S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative ­correlation between plasma H2S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD ­patients.

Abstract 13441: D-dimmer is a Predictor of Cancer Therapeutics-related Cardiac Dysfunction in Patients Treated With Cardiotoxic Chemotherapy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masayoshi Oikawa ◽  
Daiki Yaegashi ◽  
Tetsuro Yokokawa ◽  
Tomofumi Misaka ◽  
Takamasa Sato ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Troponin I ◽  
Uterine Cancer ◽  
Cancer Therapeutics ◽  
Left Ventricular ◽  
Time Dependent ◽  
Volume Index ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
D Dimer

Background: D-dimer is a sensitive biomarker for cancer-associated thrombosis, but little is known about its significance on cancer therapeutics-related cardiac dysfunction (CTRCD). Methods and Results: Consequtive 202 patients planned for cardiotoxic chemotherapy (anthracyclines, monoclonal antibodies, tyrosine kinase inhibitors, and proteasome inhibitors) were enrolled and followed up for 12 months. Cancer types were as follows: breast cancer (n=112), lymphoma (n=37), ovarian or uterine cancer (n=18), leukemia (n=13), multiple myeloma (n=6), bone cancer (n=4), and others (n=12). All patients underwent echocardiography and blood test at baseline, 3-month, 6-month, and 12-month. The patients were divided into 2 groups based on the value of D-dimer (>1.5 μg/ml or ≦1.5 μg/ml) at baseline before chemotherapy: High D-dimer group (n=52) and Low D-dimer group (n=150). At baseline, left ventricular ejection fraction (LVEF), left ventricular end-systolic volume index, and B-type natriuretic peptide levels were similar between two groups. Time-dependent decrease in LVEF was observed after chemotherapy in high D-dimer group (baseline, 66±5%; 3-month, 63±7%; 6-month, 62±7%; 12-month 62±6%; P=0.005, figure), but not in low D-dimer group. Time-dependent increase in troponin I was similarly observed after chemotherapy in both groups. The occurrence of CTRCD was higher in high D-dimer group than in low D-dimer group (11.5% vs. 4.0%, P=0.048). When we set the cut-off value of baseline D-dimer at 1.65 μg/ml from ROC analysis, sensitivity, specificity, and area under the curve to predict CTRCD were 50%, 77%, and 0.679, respectively. Multivariable logistic analysis revealed that baseline D-dimer was an independent factor to predict the decrease in LVEF more than 10% after cardiotoxic chemotherapy (odds ratio 1.210, 95% confidence interval [1.020-1.440], P=0.025). Conclusion: Baseline D-dimer is a pivotal parameter to predict CTRCD.

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.

P6276Impact of the cardiac specific deletion of AMPKalpha2 on the contractile and metabolic phenotype of the heart in male and female mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Grimbert ◽  
M N Sanz ◽  
C Rucker-Martin ◽  
M Novotova ◽  
M Gressette ◽  
...  
Keyword(s):  
Contractile Function ◽  
Left Ventricular ◽  
Metabolic Phenotype ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Male And Female ◽  
Female Mice ◽  
Sex Specificity ◽  
Specific Deletion

Abstract Introduction Mitochondrial dysfunction plays a major role in the Heart Failure (HF) pathophysiology.The AMP activated protein kinase (AMPK) is activated by a high AMP-ADP/ATP ratio and regulates a number of metabolic pathways. Many studies have highlighted a protective role of AMPK in HF, but its relevance to cardiac tissue, its metabolic part and its sex specificity are not well established. Purpose Then, the aim of this study is to determine the role of AMPK in the healthy and failing heart in male and female mice. Methods We developed and validated a mouse strain with an adult-inducible cardiac-specific deletion of AMPKα2, the major cardiac isoform, using the Cre-Lox system (40mg/kg tamoxifen injection on two consecutive days at adult age). At four months after the deletion, cardiac contractility, morphology and metabolism were studied in control and KO mice from both sexes. Results We observed only in male KO mice a decrease of left ventricular ejection fraction (−10%), an increase of the total fibrosis (+64%) and defects in mitochondrial structures. Male KO mice also showed a reduced (−28%) mitochondrial respiration via complex I associated with a different cardiolipin species distribution. Conclusion Our results reveal in adult healthy hearts, a sex-specificity in the effects of AMPKα2 deletion, leading to impaired contractile function related to metabolic and non-metabolic alterations only in male mice.

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