Hematopoietic expression of cIAP2 drives inflammation and heart failure after myocardial infarction
Ischemic heart disease, driven largely by myocardial infarction (MI), remains the leading cause of mortality and morbidity. Although early suppression of post-MI inflammation improves outcomes, current therapies have limited efficacy. Here we show that the cellular inhibitor of apoptosis 2 (cIAP2), a regulator of cell death, is upregulated after MI and promotes acute inflammation and cardiac injury. Global deletion of cIAP2, or its loss through bone marrow transfer, reduced inflammatory injury and cardiac dysfunction after MI, indicating that the cardioprotective effect of cIAP2 deficiency is primarily mediated by the hematopoietic compartment. Reduced cardiac inflammation was associated with decreased splenic myeloid cell numbers due to increased cell death and elevated expression of the death-inducing factors TRAIL and TRAIL-R2/DR5. Pharmacologic degradation of cIAP proteins after MI using Smac mimetics similarly reduced cardiac inflammation and protected against injury. Together, these findings identify cIAP2 as a key hematopoietic cell-expressed regulator of survival and inflammation and support its inhibition as a potential immunotherapeutic strategy for MI.
Authors
- Sabrina Robichaud (ORCID: https://orcid.org/0000-0001-5766-1094)
- Richard G. Jung (ORCID: https://orcid.org/0000-0002-8570-6736)
- Richard J. Seymour (ORCID: https://orcid.org/0000-0001-6126-4825)
- Katey J. Rayner (ORCID: https://orcid.org/0000-0001-6230-426X)
- Shawn T. Beug (ORCID: https://orcid.org/0000-0002-9991-3306)
- Robert G. Korneluk (ORCID: https://orcid.org/0000-0002-5675-646X)
- Eric C. LaCasse (ORCID: https://orcid.org/0000-0003-2338-1857)
- Liyong Zhang (ORCID: https://orcid.org/0000-0002-7498-6496)
- Michèle Geoffrion
- Mireille I. Ouimet (ORCID: https://orcid.org/0000-0002-6831-5047)
- Benjamin Hibbert (ORCID: https://orcid.org/0000-0003-0906-1363)
- Qiujiang Du
- Mohammad Omar AL-Khalaf
- Brian McNeill
- Caroline Beauregard
- Feng Du
- Peter P. Liu
- Simon Parlow
- Xiaoling Zhao
- David Smyth
- Tak W. Mak
Institutions
- University Health Network (CA)
- University of Ottawa (CA)
- Children's Hospital of Eastern Ontario (CA)
- Princess Margaret Cancer Centre (CA)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1038/s44161-026-00782-x
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Heart and Stroke Foundation of Canada
- Genome Canada
- Fondation Brain Canada
- Ontario Genomics
- Government of Canada
- Canada First Research Excellence Fund
- Canadian Institutes of Health Research