Prenatal 3i-0777 treatment attenuates left ventricular hypertrabeculation and dysfunction in a retinoic acid-induced mouse model
- 1Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China
Abstract
Excessive left ventricular trabeculation and thinning of the compacted myocardium arise during cardiac development and may be accompanied by myocardial dysfunction. Gestational exposure to all-trans retinoic acid (ATRA) induces a comparable phenotype in mice, providing a model for evaluating prenatal pharmacological intervention. We examined whether 3i-0777, a small-molecule enhancer of GATA4-NKX2-5 transcriptional synergy, could attenuate these structural and functional abnormalities. Pregnant C57BL/6NCrl dams were randomly assigned to untreated control, vehicle control, ATRA, or ATRA plus 3i-0777 groups (12 independent litters per group). Both ATRA-exposed groups received ATRA (50 mg/kg) on embryonic day (E)12.5. In the ATRA plus 3i-0777 group, 3i-0777 (15 mg/kg) was administered as a separate injection concurrently with ATRA at E12.5, followed by 5 mg/kg every 8 h (three doses per day) on E13.5-E15.5. At postnatal day 1, one pup was randomly selected from each litter for echocardiography and subsequent histomorphometry. The echocardiographic and histomorphometric ratios of non-compacted to compacted myocardial layer thickness (N/C ratios) were higher, and the absolute magnitude of global longitudinal strain (|GLS|) was lower, in the ATRA group than in either control group (all adjusted P < 0.001). Compared with the ATRA group, the ATRA plus 3i-0777 group had lower echocardiographic and histomorphometric N/C ratios (0.58 {+/-} 0.19 vs 2.19 {+/-} 0.18 and 0.90 {+/-} 0.33 vs 2.46 {+/-} 0.48, respectively), higher |GLS| (25.9 {+/-} 2.5% vs 15.3 {+/-} 2.7%), and a smaller left ventricular internal diameter at end-diastole (1.15 {+/-} 0.06 vs 1.42 {+/-} 0.10 mm; all adjusted P < 0.001). These findings provide proof of concept that ATRA-induced left ventricular hypertrabeculation and dysfunction can be pharmacologically attenuated in utero.
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BibTeX
@misc{shu2026prenatal,
title = {{Prenatal 3i-0777 treatment attenuates left ventricular hypertrabeculation and dysfunction in a retinoic acid-induced mouse model}},
author = {Q. Shu and Z. Wang and Q. Meng and X. Liu and L. Yin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.748426},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.748426v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Prenatal 3i-0777 treatment attenuates left ventricular hypertrabeculation and dysfunction in a retinoic acid-induced mouse model
AU - Q. Shu
AU - Z. Wang
AU - Q. Meng
AU - X. Liu
AU - L. Yin
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.748426
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.748426v1
AB - Excessive left ventricular trabeculation and thinning of the compacted myocardium arise during cardiac development and may be accompanied by myocardial dysfunction. Gestational exposure to all-trans retinoic acid (ATRA) induces a comparable phenotype in mice, providing a model for evaluating prenatal pharmacological intervention. We examined whether 3i-0777, a small-molecule enhancer of GATA4-NKX2-5 transcriptional synergy, could attenuate these structural and functional abnormalities. Pregnant C57BL/6NCrl dams were randomly assigned to untreated control, vehicle control, ATRA, or ATRA plus 3i-0777 groups (12 independent litters per group). Both ATRA-exposed groups received ATRA (50 mg/kg) on embryonic day (E)12.5. In the ATRA plus 3i-0777 group, 3i-0777 (15 mg/kg) was administered as a separate injection concurrently with ATRA at E12.5, followed by 5 mg/kg every 8 h (three doses per day) on E13.5-E15.5. At postnatal day 1, one pup was randomly selected from each litter for echocardiography and subsequent histomorphometry. The echocardiographic and histomorphometric ratios of non-compacted to compacted myocardial layer thickness (N/C ratios) were higher, and the absolute magnitude of global longitudinal strain (|GLS|) was lower, in the ATRA group than in either control group (all adjusted P < 0.001). Compared with the ATRA group, the ATRA plus 3i-0777 group had lower echocardiographic and histomorphometric N/C ratios (0.58 {+/-} 0.19 vs 2.19 {+/-} 0.18 and 0.90 {+/-} 0.33 vs 2.46 {+/-} 0.48, respectively), higher |GLS| (25.9 {+/-} 2.5% vs 15.3 {+/-} 2.7%), and a smaller left ventricular internal diameter at end-diastole (1.15 {+/-} 0.06 vs 1.42 {+/-} 0.10 mm; all adjusted P < 0.001). These findings provide proof of concept that ATRA-induced left ventricular hypertrabeculation and dysfunction can be pharmacologically attenuated in utero.
ER -