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Activation of VGLL4 Suppresses Cardiomyocyte Maturational Hypertrophic Growth
Aaron Farley1, Yunan Gao1,2, Yan Sun1
1Masonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501, USA.
Insights
Vestigial-like 4 (VGLL4) suppresses cardiomyocyte maturational hypertrophy by inhibiting the YAP/TAZ-TEAD pathway and PI3K-AKT signaling. This finding reveals VGLL4
Area of Science:
- Cardiovascular Biology
- Molecular Signaling
- Cell Growth Regulation
Background:
- Mammalian heart growth relies on cardiomyocyte (CM) size increase (maturational hypertrophy).
- The Hippo-YAP pathway regulates heart development, but its role in CM maturational hypertrophy is unclear.
- Vestigial-like 4 (VGLL4) is a Hippo-YAP pathway component that suppresses YAP/TAZ transcriptional effectors.
Purpose of the Study:
- To establish an in vitro model for studying cardiomyocyte maturational hypertrophy.
- To investigate the role of VGLL4 in cardiomyocyte maturational hypertrophy.
- To elucidate the molecular mechanisms by which VGLL4 affects CM growth.
Main Methods:
- Cultured neonatal rat ventricular myocytes (NRVMs) treated with T3, Dex, or T3/Dex.
- Assessed hypertrophic growth in NRVMs.
- Investigated VGLL4 activation effects on CMs and postnatal heart function.
- Analyzed molecular pathways including PI3K-AKT and VGLL4-TEAD interactions.
Main Results:
- T3/Dex combination treatment induced greater NRVM hypertrophy than single treatments.
- Activated VGLL4 suppressed CM maturational hypertrophy in vitro.
- In vivo, VGLL4 activation impaired heart growth and function, reducing CM size.
- VGLL4 inhibited the PI3K-AKT pathway, dependent on VGLL4-TEAD interaction.
Conclusions:
- VGLL4 acts as a suppressor of cardiomyocyte maturational hypertrophy.
- VGLL4 inhibits hypertrophy by suppressing the YAP/TAZ-TEAD complex and downstream PI3K-AKT signaling.
- This study provides insights into the regulation of heart growth via the Hippo-YAP pathway.
Abstract:
From birth to adulthood, the mammalian heart grows primarily through increasing cardiomyocyte (CM) size, which is known as maturational hypertrophic growth. The Hippo-YAP signaling pathway is well known for regulating heart development and regeneration, but its roles in CM maturational hypertrophy have not been clearly addressed. Vestigial-like 4 (VGLL4) is a crucial component of the Hippo-YAP pathway, and it functions as a suppressor of YAP/TAZ, the terminal transcriptional effectors of this signaling pathway. To develop an in vitro model for studying CM maturational hypertrophy, we compared the biological effects of T3 (triiodothyronine), Dex (dexamethasone), and T3/Dex in cultured neonatal rat ventricular myocytes (NRVMs). The T3/Dex combination treatment stimulated greater maturational hypertrophy than either the T3 or Dex single treatment. Using T3/Dex treatment of NRVMs as an in vitro model, we found that activation of VGLL4 suppressed CM maturational hypertrophy. In the postnatal heart, activation of VGLL4 suppressed heart growth, impaired heart function, and decreased CM size. On the molecular level, activation of VGLL4 inhibited the PI3K-AKT pathway, and disrupting VGLL4 and TEAD interaction abolished this inhibition. In conclusion, our data suggest that VGLL4 suppresses CM maturational hypertrophy by inhibiting the YAP/TAZ-TEAD complex and its downstream activation of the PI3K-AKT pathway.
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