Hippo pathway deficiency reverses systolic heart failure after infarction

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Cardiology

Background:

• Mammalian organs have limited regenerative capacity, with the heart being particularly susceptible to failure after injury.
• Heart failure, often resulting in mortality, is associated with upregulated Hippo pathway signaling, which inhibits adult cardiomyocyte proliferation.
• The Hippo pathway acts as a critical regulator of organ size and regeneration.

Purpose of the Study:

• To investigate the role of the Hippo pathway, specifically the Salvador (Salv) component, in the context of established ischemic heart failure.
• To determine if modulating the Hippo pathway can induce a reparative genetic program in cardiomyocytes and improve cardiac function.
• To explore the potential of gene therapy targeting the Hippo pathway for treating heart failure.

Main Methods:

• Utilized a mouse model of established ischemic heart failure following myocardial infarction.
• Deleted the Hippo pathway component Salvador (Salv) in cardiomyocytes.
• Employed translating ribosomal affinity purification to analyze cardiomyocyte-specific messenger RNA.
• Conducted genetic studies to assess the role of specific genes, such as Park2, in heart repair.
• Administered gene therapy using a virus encoding Salv short hairpin RNA.

Main Results:

• Deletion of Salv in failing mouse hearts initiated a reparative program, characterized by increased scar border vascularity and reduced fibrosis.
• Hippo-deficient cardiomyocytes exhibited increased expression of proliferative and stress response genes, including the mitochondrial quality control gene Park2.
• Genetic ablation of Park2 impaired heart repair, indicating its essential role in myocardial regeneration.
• Gene therapy with Salv short hairpin RNA improved cardiac function, whether delivered during infarct or after heart failure was established.
• The study revealed enhanced pumping function in treated mice compared to controls.

Conclusions:

• The Hippo pathway is a key regulator of cardiomyocyte proliferation and regeneration, and its inhibition can promote cardiac repair.
• Park2-mediated mitochondrial quality control is crucial for the regenerative capacity of the myocardium.
• Targeting the Hippo pathway, for example, via gene therapy with Salv short hairpin RNA, offers a promising therapeutic strategy for heart failure.
• The failing heart possesses a latent reparative potential that can be unlocked by modulating specific molecular pathways, extending beyond simple cardiomyocyte renewal.