Ninjurin1 in cardiovascular and vascular biology: From molecular mechanisms to therapeutic opportunities.

BACKGROUND

Ninjurin1 (NINJ1) is a transmembrane protein originally identified as a nerve injury-induced adhesion molecule. Recent discoveries have revealed its essential role in plasma membrane rupture (PMR) during lytic cell death, positioning NINJ1 as a critical mediator at the intersection of vascular biology, inflammation, and programmed cell death. Its complex and context-dependent biology makes it a compelling target for cardiovascular research.

METHODS

This review comprehensively synthesizes evidence from structural, molecular, cellular, and in vivo studies on NINJ1. We integrated data on NINJ1's structural biology, its cell-type-specific roles in endothelial cells, macrophages, smooth muscle cells, and pericytes, and its contributions to major cardiovascular diseases, including atherosclerosis, myocardial infarction, aortic aneurysm, and ischemia-reperfusion injury. Emerging therapeutic strategies targeting NINJ1 oligomerization were also evaluated.

RESULTS

NINJ1 exhibits a fundamental biological paradox in cardiovascular pathophysiology. In its membrane-bound form, NINJ1 transitions from an autoinhibited homodimer to an active polymeric filament upon cell death stimulation, executing PMR and releasing damage-associated molecular patterns (DAMPs) that amplify vascular inflammation. In contrast, its soluble MMP-9-cleaved ectodomain (sNINJ1) suppresses macrophage activation, attenuates monocyte-endothelial interactions, and exerts potent atheroprotective effects. NINJ1 is dynamically regulated across multiple cardiovascular pathologies and contributes to endothelial dysfunction, plaque instability, myocardial injury, and pericyte-mediated vascular remodeling.

CONCLUSIONS

NINJ1 is a pivotal and therapeutically tractable mediator of cardiovascular inflammation. Its dual roles in promoting PMR-driven DAMP release and in limiting inflammation through sNINJ1 signaling provide complementary avenues for therapeutic intervention. Strategies targeting NINJ1 oligomerization or exploiting sNINJ1-mimetic peptides hold promise for the treatment of inflammatory cardiovascular diseases and warrant further translational investigation.

KEY POINTS: Membrane-bound NINJ1 oligomerizes into amphipathic filaments to execute plasma membrane rupture (PMR) during lytic cell death, releasing DAMPs that propagate vascular inflammation across multiple cardiovascular pathologies. The soluble MMP-9-cleaved ectodomain of NINJ1 (sNINJ1) exerts anti-inflammatory and atheroprotective effects, creating a functional paradox in which a single protein can both promote and restrain cardiovascular inflammation. NINJ1 exerts cell-type-specific functions in endothelial cells, macrophages, smooth muscle cells and pericytes, contributing to atherosclerosis, myocardial infarction, aortic aneurysm and ischemia-reperfusion injury. Targeting NINJ1 oligomerization or utilizing sNINJ1-mimetic peptides represents a novel therapeutic strategy with potential for treating inflammatory cardiovascular diseases.