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ATF3 Overexpression Induces Cardiac Hypertrophy and Electrical Dysfunction through Enhanced Proliferation in Zebrafish

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE295384 | GEO | 2025/08/14

REPOSITORIES: GEO

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Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation. Three-condition experiment, MuRF1 Tg+ vs. WT mice. Biological replicates: 4 WT baseline, 3 MuRF1 Tg+ baseline, cardiac overpressure hypertrophy induced by trans-aortic banding at 1 week (3 WT, 3 MurF Tg) and 4 weeks (3 WT, 3 MurF Tg), hearts harvested. One replicate per array.

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ATF3 Overexpression Induces Cardiac Hypertrophy and Electrical Dysfunction through Enhanced Proliferation in Zebrafish

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