Silencing Survivin: a Key Therapeutic Strategy for Cardiac Hypertrophy

Area of Science:

• Cardiology
• Molecular Biology
• Gene Therapy

Background:

• Cardiac hypertrophy is a risk factor for heart failure, involving molecular, cellular, and histological changes.
• Osteopontin (OPN) and survivin (SURV) are overexpressed in heart failure, but SURV's cardiac function is unclear.
• Understanding SURV's role is crucial for developing novel therapies for cardiac hypertrophy.

Purpose of the Study:

• To investigate survivin's involvement in hypertrophic cardiomyocyte signaling.
• To assess the impact of survivin transcriptional silencing on cardiac hypertrophy.
• To lay the foundation for novel target gene therapy in cardiac hypertrophy.

Main Methods:

• Developed oligonucleotide-based molecules (molecular beacons and siRNAs) targeting SURV and OPN mRNAs.
• Evaluated diagnostic and therapeutic potential in vitro (FGF23-induced human cardiomyocytes) and in vivo (transverse aortic constriction mouse model).
• Utilized engineered erythrocytes for targeted in vivo siRNA delivery to cardiac cells.

Main Results:

• SURV knockdown negatively influenced genes involved in myocardial fibrosis in vitro.
• SURV silencing restored structural, functional, and morphometric features in vivo.
• SURV silencing normalized left ventricular mass and counteracted ejection fraction decline in a mouse model.

Conclusions:

• Survivin is a key factor in inducing cardiomyocyte hypertrophy.
• Transcriptional silencing of SURV is crucial for slowing disease progression and reversing cardiac hypertrophy.
• Targeted siRNA delivery via engineered erythrocytes shows promise for treating cardiac hypertrophy.