# Targeting Immune-Responsive Gene 1 (Irg1) and Itaconate for Cardioprotection of the Donor Heart for Transplantation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $690,954

## Abstract

Heart transplantation is considered gold standard therapy for end-stage heart failure. However, demand
currently far outstrips supply due to multiple challenges. An important limitation is the occurrence of primary
graft dysfunction (PDG) in 10-20% of patients and contributes greatly to adverse clinical outcomes and
resource utilization. PGD occurs when donor heart function and output is inadequate end organ perfusion. Risk
for significant PDG increases when donor heart preservation time is greater than 4 hours. Valproic acid (VPA),
a histone deacetylase inhibitor, is a “Food and Drug Administration (FDA)” approved drug traditionally used for
the treatment of epilepsy. We now convincingly demonstrate that addition of VPA can dramatically improve
donor heart function and improve ischemic tolerance compared to preservation using Histidine-Tryptophan-
Ketoglutarate (HTK) preservation solution alone. This was seen in murine heart reperfusion models in the
setting of ex-vivo perfusion and transplantation. Furthermore, we show evidence that VPA achieves this by
upregulating tricarboxylic acid cycle enzyme Irg1 which produces the anti-inflammatory metabolite “itaconate”.
Indeed, our cardiac reperfusion model confirms the impressive upregulation of Irg1 above baseline driven by
VPA treatment, and this was accompanied by robust activation of antioxidant pathway mechanisms through
Nrf2 transcription factor. Chromatin immunoprecipitation showed that VPA treatment increased Irg1 enhancer
activity as indicated by increased occupancy by acetylated H3K27 histone. Importantly, VPA treatment of
stored human donor hearts also upregulated Irg1 expression and decreased the expression of inflammatory
mediators suggesting translational relevance for large animal and human clinical settings. For this proposal, we
plan to: (1) Identify the cell type through which Irg1 acts and we hypothesize that it is most likely through
cardiomyocytes (CM) and endothelial cells (EC). The is achieved using transgenic mice with conditional
deficiency of Irg1 in these cell types using inducible Cre-Lox technology. We will also examine overexpression
models using adeno-associated virus mediated expression Irg1 mRNA. (2) Using cell culture, we will determine
whether Irg1/itaconate mediated alkylation modifications on Nrf2 pathway antioxidant proteins impacts their
function. We will treat cells with itaconate and then identify as well as mutate relevant alkylation modifications
sites at the cysteine residue of antioxidant proteins to determine their importance. (3) We will determine the
efficacy of VPA for improving donor heart function and ischemic tolerance in pigs and humans. We will also
corroborate mechanisms of VPA mediated cardioprotection identified in murine models. This project has critical
clinical implications such as decreasing the PGD incidence, allow transport of donor hearts over longer
distances to facilitate organ allocation, and improve clinical transplantation outcomes. ...

## Key facts

- **NIH application ID:** 10497967
- **Project number:** 1R01HL164416-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Paul Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $690,954
- **Award type:** 1
- **Project period:** 2022-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497967

## Citation

> US National Institutes of Health, RePORTER application 10497967, Targeting Immune-Responsive Gene 1 (Irg1) and Itaconate for Cardioprotection of the Donor Heart for Transplantation (1R01HL164416-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10497967. Licensed CC0.

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