Survivin determines cardiac function by controlling total cardiomyocyte number

Area of Science:

• Cardiovascular Biology
• Cell Cycle Regulation
• Molecular Cardiology

Background:

• Survivin's role in apoptosis inhibition and cell division is known in many organs, but its cardiac function remained unclear.
• Understanding survivin's cardiac function is critical for addressing heart diseases.

Purpose of the Study:

• To investigate the role of survivin in cardiac function and cardiomyocyte homeostasis.
• To explore survivin as a potential therapeutic target for myocardial regeneration.

Main Methods:

• Cardiac-specific deletion of survivin in alpha-myosin heavy chain (MHC)-survivin(-/-) mice.
• Stereological methods for cardiomyocyte quantification.
• Echocardiography, MRI, PET, and invasive catheterization for cardiac function assessment.
• Survivin small interfering RNA (siRNA) knockdown in neonatal rat cardiomyocytes.
• Adenoviral overexpression of survivin in cardiomyocytes.

Main Results:

• Cardiac-specific survivin deletion caused premature death due to reduced cardiomyocyte numbers, stemming from decreased mitotic rates and increased polyploidy without apoptosis.
• Survivin deficiency led to progressive heart failure, characterized by increased hemodynamic load per cardiomyocyte.
• Survivin overexpression inhibited apoptosis, induced DNA synthesis, and promoted cell cycle progression in cardiomyocytes.
• In human cardiomyopathy, survivin expression correlated with cardiomyocyte DNA content and was upregulated in failing hearts.

Conclusions:

• The ontogenetically determined cardiomyocyte number is a key factor in cardiac disease susceptibility.
• Survivin plays a critical role in regulating cardiomyocyte replication and survival, making it a promising target for myocardial regeneration.