Hippo pathway effector Yap promotes cardiac regeneration

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Signaling

Background:

• The adult mammalian heart exhibits limited regenerative capacity post-injury, leading to permanent cardiomyocyte loss and reduced contractility.
• Neonatal hearts can regenerate due to sustained cardiomyocyte proliferation, highlighting the importance of understanding regenerative mechanisms.
• The Hippo signaling pathway, involving Yes-associated protein (Yap), regulates cardiomyocyte proliferation and quiescence.

Purpose of the Study:

• To investigate the role of Yap and its paralog, WW domain containing transcription regulator 1 (Taz), in cardiac regeneration.
• To determine if modulating Yap activity can enhance cardiac repair in adult mammals.
• To identify the molecular mechanisms underlying Yap-mediated cardiac regeneration.

Main Methods:

• Utilized mouse models with mutant alleles of Yap and Taz to assess gene dosage effects on cardiac development and function.
• Performed cardiac-specific deletion of Yap in neonatal mice to evaluate its role in regeneration.
• Overexpressed a constitutively active form of Yap in adult mouse hearts to assess its regenerative potential after myocardial infarction.

Main Results:

• Yap and Taz exhibit redundant roles in establishing myocyte number and maintaining cardiac function.
• Cardiac-specific deletion of Yap impaired neonatal heart regeneration, leading to fibrosis.
• Forced expression of active Yap in adult hearts stimulated cardiac regeneration and improved contractility post-myocardial infarction.
• Yap's regenerative activity correlated with the activation of embryonic and proliferative gene programs in cardiomyocytes.

Conclusions:

• Yap is a key regulator of cardiac regeneration, controlling cardiomyocyte proliferation and quiescence.
• Modulating Yap activity presents a promising therapeutic strategy for enhancing cardiac repair and function.
• Targeting the Hippo-Yap pathway offers a novel entry point for developing regenerative therapies for heart disease.