ATF3 Overexpression Induces Cardiac Hypertrophy and Electrical Dysfunction through Enhanced Proliferation in Zebrafish
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PROVIDER: PRJNA1254496 | ENA |
REPOSITORIES: ENA
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Project description:Activating transcription factor 3 (ATF3) is a key regulator of gene expression in response to physiological stress across various tissues. Although its abnormal expression has been linked to cardiac dysfunction, the precise mechanisms by which ATF3 influences cardiac pathology remain unclear, with conflicting findings in the literature. To address this, we developed a cardiac-specific ATF3-expressing zebrafish line, Tg (myl7:ATF3), using the zebrafish model as a well-established vertebrate system for cardiovascular research. Compared to wild-type (WT) siblings, Tg (myl7:ATF3) zebrafish exhibited significant pathophysiological changes, including cardiac hypertrophy and features resembling hypertrophic cardiomyopathy (HCM). Histological analysis revealed increased fibrotic scarring, sarcomere disorganization, and elevated expression of heart failure gene markers (nppa and nppb). Notably, electrocardiogram (ECG) measurements showed that ATF3 overexpression led to symptoms resembling Long QT Syndrome (LQTS), indicating electrical dysfunction. Transcriptome analysis further revealed downregulation of apoptosis-related genes and upregulation of proliferation-related genes in transgenic zebrafish hearts. These findings suggest that stress-induced ATF3 expression contributes to cardiac hypertrophy through enhanced cardiomyocyte proliferation, providing novel insights into its role in cardiovascular disease progression.
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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.
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Project description:A molecular and bioinformatic pipeline permitting comprehensive analysis and quantification of myocardial miRNA and mRNA expression with next-generation sequencing was developed and the impact of enhanced PI3Kalpha signaling on the myocardial transcriptome signature of pressure overload-induced pathological hypertrophy was explored. miRNA and mRNA-Seq were carried out in four groups of mouse LV samples: WT sham, WT+TAC, caPI3Kalpha sham, caPI3Kalpha+TAC
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Project description:Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven pro-inflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3-/- neutrophil recruitment to wild type lungs. In vitro, ATF3-/- neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3-/- neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3-/- and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production, but promotion of neutrophil chemotaxis. Ly6G+ neutrophils were purified by magnetic beads from WT or ATF3 KO bone marrow and RNA was immediately isolated for global gene expression using microarrays.
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Project description:Cardiac hypertrophy can lead to heart failure, and is induced either by physiological stimuli eg postnatal development, chronic exercise training or pathological stimuli eg pressure or volume overload. Majority of new therapies for heart failure has mixed outcomes. A combined mouse model and oligo-array approach are used to examine whether phosphoinositide 3-kinase (p110-alpha isoform) activity is critical for maintenance of cardiac function and long-term survival in a setting of heart failure. The significance and expected outcome are to recognise genes involved in models of heart failure ie pathological- vs physiology-hypertrophy, and examine the molecular mechanisms responsible for such activity. Growth of the heart can be induced by physiological stimuli e.g., postnatal development, chronic exercise training, or pathological stimuli e.g., pressure or volume overload. Physiological hypertrophy (“good”) is characterised by a normal organisation of cardiac structure, and normal or enhanced cardiac function. In comparison, pathological hypertrophy (”bad”) is associated with fibrosis, cardiac dysfunction, and increased morbidity and mortality. The mechanistic process which allows the heart to enlarge in response to physiological stimuli while maintaining normal or enhanced function is of great clinical relevance because one potential therapeutic strategy is to inhibit the pathological growth process while augmenting the physiological growth process. One of the major process that regulate heart size is by phosphoinositide 3-kinase (PI3K). Thus the end goal of this project is to determine whether the p110 alpha isoform of PI3K could be a potential tool for augmenting physiological growth and improving cardiac function of the failing diseased heart, and to examine the underlying mechanisms responsible. Keywords: Disease progression analysis
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