Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure

Area of Science:

• Cardiovascular Biology
• Extracellular Vesicles
• Molecular Medicine

Background:

• Heart failure (HF) is a major global health concern.
• Extracellular vesicles (EVs), including exosomes, play a role in cardiac disease communication.
• The impact of systemic exosome biogenesis inhibition in HF models is not well understood.

Purpose of the Study:

• Investigate the role of circulating exosomes in a mouse model of HF.
• Evaluate tipifarnib, an exosome biogenesis inhibitor, for treating HF.
• Determine if tipifarnib affects exosome cargo, specifically microRNAs.

Main Methods:

• Utilized a mouse transverse aortic constriction (TAC) model of HF.
• Administered tipifarnib to TAC mice and assessed cardiac function, histology, and plasma exosomes.
• Analyzed exosome and cardiac tissue miRNA profiles, focusing on miR 331-5p.

Main Results:

• TAC increased circulating exosomes, cardiac dysfunction, hypertrophy, and fibrosis.
• Exosomes from TAC mice induced cardiac dysfunction and hypertrophy in naive mice.
• Tipifarnib treatment reduced exosomes, improved cardiac function, and attenuated fibrosis.
• Tipifarnib normalized miR 331-5p levels, which were downregulated in TAC exosomes and cardiac tissue.
• miR 331-5p targets HOXC8, a fibrosis regulator, and its restoration by tipifarnib mitigated fibrosis.

Conclusions:

• Systemic exosome biogenesis inhibition is a promising therapeutic strategy for HF.
• Tipifarnib effectively reduces cardiac remodeling and fibrosis in HF by modulating exosome cargo.
• Targeting exosome pathways offers a novel approach to managing pressure-induced heart failure.