Alkaline ceramidase 1-mediated platelet ceramide catabolism mitigates vascular inflammation and abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) is a highly lethal vascular disease. The role of platelets in AAA remains incompletely understood. Here we show that platelet ceramides, rather than other phospholipids, were elevated in an angiotensin II (AngII)-induced AAA murine model and in patients with AAA by using targeted lipidomic analysis. Among key ceramide metabolism enzymes, alkaline ceramidase 1 (Acer1) hydrolyzing ceramides were exclusively downregulated in AAA platelets. Platelet-specific Acer1 knockout mice were more susceptible to AAA upon AngII infusion without affecting hemostasis and thrombosis. Mechanistically, Acer1 deficiency in platelets facilitated platelet pro-inflammatory cytokine secretion as well as P-selectin-mediated circulating platelet-leukocyte aggregation and infiltration in aortic walls via the ceramide-p38 MAPK signaling axis. Of note, AngII repressed Acer1 expression in platelets by decreasing HuR-dependent mRNA stability. In conclusion, Acer1-mediated ceramide degradation in platelets exhibited anti-inflammatory effects and ameliorated AAA formation, potentially serving as a therapeutic target for AAA and other inflammatory vascular diseases.