scholarly journals Exploration of the Amino Acid Metabolic Signature in Anthracycline-induced Cardiotoxicity Using an Optimized Targeted Metabolomics Approach Based on UPLC-MS/MS

2021 ◽  
Author(s):  
Wendi Li ◽  
Shanshan Li ◽  
Zhenju Cao ◽  
Yi Sun ◽  
Wei Qiu ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Clinical Stage ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Normal Structure ◽  
Left Ventricular ◽  
Term Survival ◽  
Cellular Models ◽  
Metabolic Signature ◽  
H9c2 Cardiomyocytes

Abstract Background: Although anthracyclines improve the long-term survival rate of patients with cancer, severe and irreversible myocardial damage limits their clinical application. Amino acids (AAs) play critical roles in protein synthesis, energy generation, and metabolism, as well as maintenance of the normal structure of cardiomyocytes. Conversely, AA metabolism in cardiomyocytes can be altered under pathological conditions. Therefore, exploring the AA metabolic signature in anthracycline-induced cardiotoxicity (AIC) is important for identifying novel mechanisms.Methods: We established mouse and cellular models of Adriamycin (ADR)-induced cardiac injury. Using a targeted AA metabolomics approach based on ultra-performance lipid chromatography–tandem mass spectrometry (UPLC-MS/MS), we quantified more than 120 AA metabolites through derivatization-assisted sensitivity enhancement with 5-aminoisoquinolyl-N-hydroxysuccinimidyl carbamate (5-AIQC). The AA metabolic signatures in the sera of AIC mice and supernatant samples of ADR-treated H9c2 cardiomyocytes were analyzed. Results: The levels of 14 AA metabolites were altered in ADR-treated mice (p < 0.05). l-2-aminoadipic acid (2-AA) was one of the most suppressed metabolites in AIC. Pre-treatment with 2-AA failed to alter ADR-induced cardiac function impairment, but it exacerbated the ADR-induced decrease of left ventricular anterior wall thickness, indicating that 2-AA might contribute to AIC. Via bioinformatics analysis, we identified nine differential AA metabolites in mice, namely l-glutamic acid, l-lysine, l-serine, l-tryptophan, l-methionine, l-histidine, l-asparagine, l-tyrosine, and O-phosphorylethanolamine, and five differential AA metabolites in ADR-treated H9c2 cardiomyocytes, specifically l-tyrosine, l-alanine, l-glutamine, l-serine, and l-glutamic acid. Three AAs with increased levels (l-glutamate, l-serine, and l-tyrosine) overlapped in the two models, suggesting a possible mechanism of AA metabolic impairment during AIC. The metabolic pathways perturbed by AIC involved aminoacyl-tRNA biosynthesis and alanine, aspartate, and glutamate metabolism. Conclusions: These data indicate that a targeted AA metabolomics approach based on UPLC-MS/MS can be used to explore the AA metabolic signature and identify novel mechanisms of AIC, which may provide new clues for the prevention and treatment of this condition in the early clinical stage.

IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

2007 ◽  
Vol 293 (4) ◽  
pp. H2248-H2253 ◽  
Author(s):  
Nancy C. Moss ◽  
William E. Stansfield ◽  
Monte S. Willis ◽  
Ru-Hang Tang ◽  
Craig H. Selzman
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Nuclear Factor Κb ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Artery Ligation ◽  
Cardiac Morbidity

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-κB (NF-κB) has been implicated as a key mediator of reperfusion injury. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated IκBα and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-κB activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.

scholarly journals Peripheral Blood MicroRNAs as Potential Biomarkers of Myocardial Damage in Acute Viral Myocarditis

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 420
Author(s):  
Maria Marketou ◽  
Joanna Kontaraki ◽  
Alexandros Patrianakos ◽  
George Kochiadakis ◽  
Ioannis Anastasiou ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Troponin I ◽  
Left Ventricular Systolic Dysfunction ◽  
Global Longitudinal Strain ◽  
Viral Myocarditis ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Cardiovascular Development ◽  
Acute Viral Myocarditis

Background: microRNAs (miRs) have emerged as important modulators of cardiovascular development and disease. Our aim was to determine whether cardiac-related miRs such as miR-21-5p and miR-1-3p were differentially expressed in acute viral myocarditis and whether any of them was related with the extent of myocardial damage and left ventricular dysfunction. Methods: We enrolled 40 patients with acute viral myocarditis. Blood samples were taken on admission and miRs expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Results: miR-21-5p, miR-1-3p were significantly elevated in acute myocarditis. miR-21-5p levels showed a strong correlation with global longitudinal strain (r = 0.71, p < 0.01), while miR-1-3p had significant correlations with troponin I (r = 0.79, p < 0.01). Conclusions: The expression of miR-21-5p and miR-1-3p in peripheral blood is increased in acute viral myocarditis, and this increase is correlated with myocardial damage and indicative of left ventricular systolic dysfunction in these patients.

scholarly journals Association of Cardiac Injury and Malignant Left Ventricular Hypertrophy With Risk of Heart Failure in African Americans

2019 ◽  
Vol 4 (1) ◽  
pp. 51 ◽  
Author(s):  
Ambarish Pandey ◽  
Neil Keshvani ◽  
Colby Ayers ◽  
Adolfo Correa ◽  
Mark H. Drazner ◽  
...  
Keyword(s):  
Heart Failure ◽  
African Americans ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Cardiac Injury ◽  
Left Ventricular

HDL Cholesterol Level Predicts Survival in Men After Coronary Artery Bypass Graft Surgery

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
JoAnne Micale Foody ◽  
Francis D. Ferdinand ◽  
Gregory L. Pearce ◽  
Bruce W. Lytle ◽  
Delos M. Cosgrove ◽  
...  
Keyword(s):  
Artery Bypass ◽  
Bypass Graft ◽  
Hdl Cholesterol ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Term Survival ◽  
Ventricular Ejection Fraction ◽  
Low Hdl ◽  
History Of ◽  
Extent Of Disease

Background —HDL cholesterol (HDL-C) is an important independent predictor of atherosclerosis, yet the role that HDL-C may play in the prediction of long-term survival after CABG remains unclear. The risk associated with a low HDL-C level in post-CABG men has not been delineated in relation to traditional surgical variables such as the use of arterial conduits, left ventricular function, and extent of disease. Methods and Results —We performed a prospective, observational study of 432 men who underwent CABG between 1978 and 1979 in whom preoperative HDL-C values were available. Baseline lipid and lipoprotein values, history of diabetes mellitus and hypertension, left ventricular ejection fraction, extent of disease, and use of internal thoracic arteries were recorded. Hazard ratios (HRs) were determined in the patients with and without a low HDL-C level, which was defined as the lowest HDL-C quartile (HDL-C ≤35 mg/dL). After adjustment for age, as well as for baseline metabolic parameters and surgical variables just noted, HDL-C corresponded to both overall (HR 0.40, CI 0.20 to 0.83, P =0.01) and event-free (HR 0.41, CI 0.24 to 0.70, P =0.001) survival. Patients with a high HDL-C level (>35 mg/dL) were 50% more likely to survive at 15 years than were patients with low HDL-C level (≤35 mg/dL) (74% versus 57% adjusted survival, respectively; HR 1.72, P =0.005). In addition, HDL-C showed a strong effect on time-to-event survival such that patients with an HDL-C level of >35 mg/dL were 50% more likely to survive without a subsequent myocardial infarction or revascularization (HR 1.42, P =0.02). Conclusions —HDL-C is an important predictor of survival in post-CABG patients. In this study of >8500 patient-years of follow-up, HDL-C was the most important metabolic predictor of post-CABG survival. One third fewer patients survive at 15 years if their HDL-C levels are ≤35 mg/dL at the time of CABG. The measurement of HDL-C provides a compelling strategy for the identification of high-risk subsets of patients who undergo CABG.

Abstract 1712: The P2Y 12 Antagonist Cangrelor and the GP IIb/IIIa Blocker Abciximab Reduce Platelet-Mediated Myocardial Injury After Ischemia and Reperfusion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jose A Barrabes ◽  
Javier Inserte ◽  
Maribel Mirabet ◽  
Adoracion Quiroga ◽  
Victor Hernando ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Myocardial Salvage ◽  
Ischemia And Reperfusion ◽  
Activated Platelets ◽  
Rat Hearts ◽  
Developed Pressure ◽  
Enddiastolic Pressure ◽  
Isolated Rat

Objective: Platelets activated during experimental acute myocardial infarction (AMI) contribute to myocardial injury. We aimed to investigate whether platelets from patients with AMI increase myocardial damage after transient ischemia in isolated rat hearts and the modification of this effect by the P2Y 12 receptor antagonist cangrelor and the GPIIb/IIIa receptor blocker abciximab. Methods: Platelets were obtained from 9 AMI patients (7 thrombolyzed, all on aspirin) within 24 h after symptom onset. Incubation with 100 μM cangrelor or 50 μg/ml abciximab resulted, respectively, in 78 ± 4 and 90 ± 2% inhibition of aggregation (optical aggregometry). Isolated rat hearts (four simultaneous experiments per patient) were subjected to 40 min of global ischemia and 60 min of reperfusion. Hearts received no additional intervention (Control) or were infused during the 5 min prior to ischemia with platelets (22.5x10 6 /min), either untreated or treated with cangrelor or abciximab. Results: P-selectin expression (flow cytometry) in isolated platelets before infusion was 31 ± 3% (P = NS between groups). Platelets augmented myocardial injury, as demonstrated by worse left ventricular developed pressure (LVDevP), higher left ventricular enddiastolic pressure (LVEDP) and coronary resistance, and greater LDH release and infarct size (TTC staining), and both cangrelor and abciximab greatly attenuated these effects (Table ). Conclusions: Activated platelets from patients with AMI increase myocardial injury after ischemia and reperfusion, and cangrelor and abciximab attenuate this effect. The results support the notion that very early antiplatelet treatment may increase myocardial salvage by direct effects on the microcirculation in these patients.

Abstract 060: CCN1/a 6 β 1 Mediates Myocardial Injuries Induced by Work Overload or by Doxorubicin in Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Pei-Ling I Hsu ◽  
Fan-E Mo
Keyword(s):  
Myocardial Injury ◽  
Fas Ligand ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Myocardial Damage ◽  
Matricellular Protein ◽  
Work Overload ◽  
Myocardial Injuries ◽  
Injury Models

Introduction: Matricellular protein CCN1 is expressed in myocardial infarction, pressure overload, and ischemia in mice, and in patients with a failing heart. Despite its well-documented angiogenic activities, CCN1 promotes fibroblast apoptosis in some contexts. The role of CCN1 in an injured heart was not clear. We assessed the hypothesis that CCN1 plays a detrimental role and mediates cardiac injury through its proapoptotic activities. Methods and Results: To test the role of CCN1 in cardiac injury, we employed two different myocardial injury models in mice, including a work-overload-induced injury created by isoproterenol treatment (ISO; 100 mg/kg/day; s.c. for 5 days; n= 6 for each group) and an injury induced by the cardiotoxicity of doxorubicin (DOX, single dose of 15 mg/kg; i.p. sacrificed after 14 days). Ccn1 expression was induced in the damaged myocardium in both injury models. A line of knock-in mice carrying an apoptosis-defective Ccn1 mutant allele, Ccn1-dm , which has disrupted integrin α 6 β 1 binding sites, were tested in the ISO- or DOX -induced cardiac injury. Myocardial damage was seen in tissues from wile-type (WT) hearts after receiving ISO. Ccn1 dm/dm (DM) mice possessed remarkable resistance against ISO or DOX treatments and exhibited no tissue damage or fibrosis compared to WT mice after H&E or Masson’s trichrome stainings. DM mice were resistant to both ISO- and DOX-induced cardiac cell apoptosis, indicating that CCN1 is critically mediating cardiomyocyte apoptotic death in cardiac injury. Moreover, we found that death factor Fas ligand (FasL) and its receptor Fas were upregulated in WT mice receiving ISO or DOX treatments by immunohistochemical staining, compared with the PBS-control. 8-OHdG-positive, a marker for oxidative stress, cardiomyocytes were increased by ISO or DOX treatments as well. In contrast, the expression of Fas/FasL, and the 8-OHdG-positive cardiomyocytes in the myocardium of DM mice were not changed by ISO or DOX. Conclusions: We identify CCN1 as a novel pathophysiological regulator of cardiomyocyte apoptosis in cardiac injury. Blocking apoptotic function of CCN1 effectively prevents myocardial injury in mice. CCN1 and its receptor α 6 β 1 represent promising future therapeutic targets in cardiac injury.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

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