Immune Targeting of Oligomeric Ninjurin 1 Protects Against Myocardial Infarction in Mice

Plasma membrane rupture (PMR) amplifies lytic cell death by releasing intracellular damage-associated molecules that propagate inflammation.Ninjurin 1 (NINJ1) has emerged as a key executioner of PMR during lytic cell death of non-cardiac cells, including leukocytes, macrophages, endothelial cells, smooth muscle cells, and pericytes, where its oligomerization enables the release of damage-associated molecules such as HMGB1, LDH and/or IL-18, raising the possibility that NINJ1-mediated PMR may also be relevant to cardiovascular injury 1,2,3 .Although gasdermin-dependent pyroptotic signaling contributes to ischemic myocardial injury, whether myocardial infarction (MI) induces cardiac NINJ1 oligomerization, and whether this process can be therapeutically targeted, remains unknown 4 .We therefore tested the hypothesis that MI promotes cardiac NINJ1 oligomerization and that blockade of oligomeric NINJ1 suppresses PMR-associated injury and reduces post-MI remodeling.We first examined NINJ1 oligomerization in ischemia/reperfusion (I/R)-injured mouse hearts with a MI model, i.e., 120 minutes of left coronary artery occlusion followed by reperfusion, performed in accordance with institutional guidelines with approval by the Institutional Animal Care and Use Committee of University of Missouri (Approval #40285).Immunoblotting revealed increased NINJ1 expression along with accumulation of BS3-crosslinked high-molecular weight NINJ1 complexes 5 in the infarcted myocardium 3 day after I/R-induced MI (Figure 1A).