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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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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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2022-09-20 | MTBLS795 | MetaboLights

Gene profiling of Hand2 target genes and transcriptional regulation of Hand2 expression in the postnatal myocardium

Project description:In humans, cardiac hypertrophy is the principal risk factor for the development of overt heart failure and sudden cardiac death from lethal arrhythmias. Although aberrant reactivation of fetal² gene programs is intricately linked to maladaptive hypertrophy of postnatal cardiomyocytes, loss of cardiac function and heart failure, the transcription factors driving these gene programs remain ill defined. We report that the basic helix-loop-helix (bHLH) transcription factor dHAND/Hand2 is re-expressed in the mammalian postnatal myocardium in response to stress signaling. Interestingly, mutant mice overexpressing Hand2 in otherwise healthy ventricular myocytes developed a phenotype of pathological hypertrophy. In contrast, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. These data suggest a critical role for the Hand2 transcription factor during hypertrophic remodeling and heart failure. To gain more mechanistically insight in the processes underlying heart failure, we here identified Hand2 target genes by microarray gene expression profiling. RNA samples were collected 4 weeks after sham or TAC surgery (to induce pressure overload) of both tamoxifen-treated Hand2f/f (WT) and MCM-Hand2f/f (KO) mice.

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Transcription profiling of pig intestinal developmental process in different sucking phases

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Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death

Project description:Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation, cardiac fibrosis and death in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Both pharmacological and genetic inhibition of phytosterol absorption prevented the induction of both pathways. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These phytosterolemia-associated comorbidities provide novel insight into the underlying pathophysiological mechanism that predispose these patients to increased risk of sudden cardiac death.

2021-08-31 | GSE173123 | GEO

Foxa2 identifies a novel ventricular-specific cardiac progenitor population during gastrulation.

Project description:The recent identification of novel progenitor populations that contribute to the developing heart in a distinct temporal and spatial manner has fundamentally improved our understanding of cardiac development. However, little remains known about cardiac specification events prior to the establishment of the heart tube, or the mechanisms that direct atrial versus ventricular specification. We have identified a novel progenitor population that gives rise specifically to cardiovascular cells of the ventricles but not the atria, and to the epicardium of the differentiated heart. We determined that this cell population is first specified during gastrulation, when it transiently expresses Foxa2, a gene not previously implicated in cardiac development. Using chimeric mosaic analysis we further demonstrate that Foxa2 is cell-autonomously required for the development of ventricular cells. Finally, we reveal the existence of an analogous Foxa2+ cardiac mesoderm population during in vitro differentiation from embryonic stem cells and illustrate that these cells express genes relevant for heart development. Our data thus describe the first progenitor population identified as early as gastrulation that displays ventricular-specific differentiation potential. Together, these findings provide important new insights into the developmental origin of ventricular and atrial myocytes, and will lead to the establishment of new strategies for generating these cell types from pluripotent stem cells.

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