# Hematopoietic expression of cIAP2 drives inflammation and heart failure after myocardial infarction

## TL;DR

This study shows that cIAP2, a protein involved in cell survival, worsens heart damage after a heart attack and suggests that blocking it could help prevent heart failure.

## Contribution

The study identifies cIAP2 as a hematopoietic cell-expressed regulator of inflammation and injury after MI, and proposes its inhibition as a novel immunotherapeutic strategy.

## Key findings

- cIAP2 is upregulated after MI and promotes acute inflammation and cardiac injury.
- Deleting cIAP2 or using Smac mimetics reduces inflammation and protects against cardiac injury.
- cIAP2's effects are primarily mediated through the hematopoietic compartment.

## Abstract

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.

Smyth et al. demonstrate that a cellular inhibitor of apoptosis, cIAP2, exacerbates inflammation and cardiac injury after myocardial infarction and that its inhibition, either genetically or via Smac mimetics, offers a promising immunotherapeutic strategy to reduce post-MI damage and progression to heart failure.