Role of the Elastase-2 (Ela-2)/OPN-N cascade in abdominal aortic aneurysm pathobiology: A human-to-mouse translational study.

Abdominal aortic aneurysm (AAA) is driven by chronic inflammation and extracellular matrix (ECM) degradation. Elastase-2 (Ela-2) is a conserved chymotrypsin-like serine protease encoded by the human gene CELA2A and its murine ortholog Cela2a, and it generates angiotensin II and contributes to cardiovascular remodeling. However, its role in AAA remains undefined. This study characterizes Ela-2 in human (AAA n = 41; controls n = 21) and experimental AAA. Ang II-infused wild-type (Wt) and Cela2a Knockout (Cela2a-/-, Cela2a KO) mice were analyzed for Ela-2 expression, cytokines, and ECM markers. Human AAA showed marked Ela-2 upregulation, elevated IL-6/IL-8/CCL5, macrophage infiltration, and increased Osteopontin N-terminal fragment (OPN-N) alongside MMP-2/9 activity. WT + Ang II mice recapitulated this phenotype with aortic dilation, inflammation, ECM disruption, and OPN-N accumulation, whereas Cela2aKO mice +Ang II were protected. Structural modeling confirmed active site conservation enabling angiotensin cleavage and ECM proteolysis. Ela-2, encoded by the human gene CELA2A, emerges as a key proteolytic driver of AAA progression and a promising therapeutic target.