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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Cardiac gene expression analysis in porcine model of heart failure

ABSTRACT: A gene expression topology of the developing, postnatal and diseased heart resulted in re-interpretation of ventricular remodeling in terms of rearrangement of key gene regulatory networks that are imbalanced, attenuated, or abnormally activated in the failing myocardium. The underlying principle, “Shaping the heart in development and disease” becomes a focus of current cardiovascular research with the goal of developing innovative diagnostic and therapeutic strategies to combat cardiovascular disease. In this line, our interests focus on regulatory molecular pathways and identification of novel candidate genes associated with ventricular remodeling in normal and pathological states. The general goal of the project was to establish a piglet model of heart failure induced by the cardiotoxic agent Doxorubicin. Transcriptomic analysis on Affymetrix GeneChip Porcine Genome Array was used to used to identified the genes associated with pathological ventricular remodeling. Six 8-day old piglets were randomized in two groups, the experimental group (n=3) received a single intravenous administration of 2.0 mg/kg Doxorubicin, whereas the control group (n=3) was injected with PBS. Piglets were euthanized 3 weeks later to harvest cardiac tissue for RNA isolation. Piglets were used in accordance with protocols approved by the Institutional Animal Care and Use Ethical Committee.

ORGANISM(S): Sus scrofa

SUBMITTER: Mario Torrado

PROVIDER: E-GEOD-30110 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Cardiac gene expression analysis in porcine model of heart failure

Project description:A gene expression topology of the developing, postnatal and diseased heart resulted in re-interpretation of ventricular remodeling in terms of rearrangement of key gene regulatory networks that are imbalanced, attenuated, or abnormally activated in the failing myocardium. The underlying principle, “Shaping the heart in development and disease” becomes a focus of current cardiovascular research with the goal of developing innovative diagnostic and therapeutic strategies to combat cardiovascular disease. In this line, our interests focus on regulatory molecular pathways and identification of novel candidate genes associated with ventricular remodeling in normal and pathological states. The general goal of the project was to establish a piglet model of heart failure induced by the cardiotoxic agent Doxorubicin. Transcriptomic analysis on Affymetrix GeneChip Porcine Genome Array was used to used to identified the genes associated with pathological ventricular remodeling.

2012-06-01 | GSE30110 | GEO

The role of stretch, tachycardia and sodium-calcium exchanger in induction of early cardiac remodeling

Project description:Accute stretch and tachycardia are capable of inducing pathological excitation transcription coupling - an early invent before structural cardiac remodeling which transitions to heart failure. The sodium calcium exchanger is a key player in maintaining calcium homeostasis and is implicated in pathological signaling during heart failure. Neonatal rat ventricular cardiomyocytes (NRVCM) were subjected to mechanical stress and high freqency elecrical stimulation to study genes regulated during the early phase of trigger induced cardiac remodeling. Inhibition of the sodium calcium exchanger was used in an attempt to supress the early remodeling process and gain insight into the pathological signaling pathway.

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Prdm16 deficiency leads to age-dependent cardiac hypertrophy, adverse remodeling, mitochondrial dysfunction, and heart failure

Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.

2020-09-21 | GSE153988 | GEO

Cardiac Remodeling During Pregnancy With Metabolic Syndrome: Prologue of Pathological Remodeling

Project description:The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders. The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet–feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)–induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat). Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery. These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.

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Human Induced Pluripotent Stem Cells Recapitulate Breast Cancer Patients’ Predilection to Doxorubicin-Induced Cardiotoxicity

Project description:Doxorubicin (Adriamycin) is an anthracycline chemotherapy agent effective in treating a wide range of malignancies1 with a well-established dose-response cardiotoxic side-effect that can lead to heart failure2-4. Even at relatively low cumulative doses of 200–250 mg/m2, the risk of cardiotoxicity is estimated at 7.8% to 8.8%4,5. Doxorubicin-induced cardiotoxicity (DIC) can range from asymptomatic reductions in left ventricular ejection fraction (LVEF) to highly symptomatic heart failure6,7. At present, it is not possible to predict which patients will be affected by DIC or adequately protect patients who are at risk for suffering this devastating side-effect8. Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate individual patients’ predilection to DIC at the single cell level. hiPSC-CMs derived from breast cancer patients who suffered clinical DIC are consistently more sensitive to doxorubicin toxicity, demonstrating decreased cell viability, mitochondrial/metabolic function, calcium handling, and antioxidant pathway gene expression, along with increased reactive oxygen species (ROS) production compared to hiPSC-CMs from patients who did not experience DIC. Together, our data indicate that hiPSC-CMs are a suitable platform for identifying and verifying the genetic basis and molecular mechanisms of DIC.

2016-04-18 | GSE76314 | GEO

Cardiac Metabolic Deregulation Induced by the Tyrosine Kinase Receptor Inhibitor Sunitinib is rescued by Endothelin Receptor Antagonism

Project description:The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardiovascular system. Here, we explored the cardiotoxicity of the antiangiogenic therapy, sunitinib, in the mouse heart from a diagnostic and therapeutic perspective. We showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis and reduced left ventricular ejection fraction as demonstrated by echocardiography. The capacity of positron emission tomography with [18F]fluorodeoxyglucose to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment. Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes. Co-administration of macitentan, the endothelin receptor antagonist, to sunitinib-treated animals prevented both metabolic defects, restored glucose uptake and cardiac function, and prevented myocardial fibrosis. These results support the endothelin system in mediating the cardiotoxic effects of sunitinib and endothelin receptor antagonism as a potential therapeutic approach to prevent cardiotoxicity. Furthermore, metabolic and functional imaging can monitor the cardiotoxic effects and the benefits of endothelin antagonism in a theranostic approach.

2017-07-14 | PXD006888 | Pride

Effect of doxorubicin and SPEDOX-6 on human iPSC-derived cardiac spheroids comprised of cardiomyocytes, endothelial cells, and fibroblasts.

Project description:The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We utilized human induced pluripotent stem cell-derived multi-lineage cardiac spheroids (hiPSC-CSs) to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated doxorubicin (SPEDOX-6), to standard unformulated (UF) DOX using RNA-sequencing. The cardiac spheroids are comprised of hiPSC-derived cardiomyocytes (hiPSC-CMs), hiPSC-derived endothelial cells (ECs), and hiPSC-derived cardiac fibroblasts (CFs) at an 8:1:1 ratio.

2023-07-01 | GSE235470 | GEO

Incidence of cardiovascular events in patients with esophageal/stomach or colorectal cancer treated by trifluridine/tipiracil +/- oxaliplatin after an episode of cardiac angina-related thoracic pain in the adjuvant or metastatic setting.

Project description:Primary objectives: To assess the rate of cardiovascular events in patients treated with trifluridine/tipiracil +/- oxaliplatin over a 3-month period.Cardiovascular events are defined as follows:- Acute coronary syndrome without ST segment elevation,- Acute coronary syndrome with ST segment elevation,- Acute myocardial infarction,- Heart failure,- Arrhythmia (atrial fibrillation, flutter, junctional tachycardia, ventricular tachycardia), - Cardiovascular death,- Sudden death of any cause. Primary endpoints: The rate of cardiovascular events at 3 months

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mRNA array profiling on human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin

Project description:Cardiomyocytes derived from human pluripotent stem cells were exposed to the cardiotoxic drug Doxorubicin in order to assess the utility of this cell system as a model for drug-induced cardiotoxicity. Cells are exposed to different concentrations of doxorubicin for up to 48 hours followed by a 12 days recovery period.

2017-12-19 | E-MTAB-6045 | biostudies-arrayexpress

MicroRNA array profiling on human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin

2017-10-28 | E-MTAB-6052 | biostudies-arrayexpress

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