Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function

Area of Science:

• Cardiovascular Biology
• Immunometabolism
• Transplantation Science

Background:

• Donor heart preservation quality is critical for transplant success, with prolonged preservation (>4 hours) linked to primary graft dysfunction (PGD).
• Geographical limitations and transport time constraints hinder optimal donor-recipient matching, leading to underutilization of donor hearts.
• Metabolic reprogramming offers a potential strategy to enhance organ preservation and improve transplant outcomes.

Purpose of the Study:

• To investigate the role of immune response gene 1 (IRG1) and its product itaconate in donor heart preservation.
• To determine if valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, can up-regulate IRG1 and improve heart function after prolonged preservation.
• To explore the underlying antioxidant and anti-inflammatory mechanisms involved in VPA-mediated cardioprotection.

Main Methods:

• Administered VPA in histidine-tryptophan-ketoglutarate solution for donor heart preservation.
• Assessed IRG1 transcript expression and histone modifications (acetylated H3K27) at the IRG1 enhancer in human donor hearts.
• Evaluated Nrf2 pathway activation, antioxidant protein expression (HO1, SOD1), and itaconate levels in VPA-treated mouse and human hearts.
• Utilized Irg1 knockout mice to confirm the necessity of IRG1 for VPA's protective effects.
• Tested VPA efficacy in pig donor hearts using an ex vivo cardiac perfusion system at 4 and 10 hours of preservation.

Main Results:

• VPA treatment increased IRG1 transcript expression and itaconate levels in human donor hearts, associated with enhanced H3K27 acetylation at the IRG1 enhancer.
• In mice, VPA-induced IRG1 up-regulation promoted Nrf2 nuclear translocation and increased expression of antioxidant proteins HO1 and SOD1.
• The cardioprotective and antioxidant effects of VPA were abolished in Irg1 knockout mice.
• VPA treatment increased itaconate availability and reduced succinate accumulation during preservation in human hearts.
• VPA improved the function of pig donor hearts after 4 and 10 hours of preservation in an ex vivo system.

Conclusions:

• Metabolic reprogramming via VPA-mediated IRG1 up-regulation enhances donor heart preservation by boosting antioxidant defenses and reducing cellular stress.
• Itaconate, produced by IRG1, plays a key role in the cardioprotective effects of VPA, potentially through inhibition of succinate dehydrogenase.
• Augmenting cardioprotective immune-metabolomic pathways represents a promising therapeutic strategy to improve donor heart quality and increase transplant success rates.