Abstract
BACKGROUND AND AIMS: Vascular inflammation is a hallmark of abdominal aortic aneurysms (AAA) but the mechanism of these effects is undefined. High-mobility group box 1 (HMGB1) has potent inflammatory properties and has been implicated in various vascular diseases. We determined a role for HMGB1 in AAA pathogenesis utilizing an antisense oligonucleotide (ASO) to inhibit synthesis of the protein. METHODS AND RESULTS: To identify molecular signatures and biological pathways associated with AAA, we analyzed RNA sequencing (RNA-seq) data from patients with AAA (GSE57691) and mice with angiotensin II (AngII)-induced AAA (GSE17901) obtained from the GEO database. Transcriptomic analysis revealed a marked upregulation of HMGB1 in both human and mouse aneurysmal tissue. AngII infusion into male LDLR-/- mice significantly increased HMGB1 protein abundance in the abdominal aorta after 7 days consistent with a role in AAA initiation. To assess the functional role of HMGB1 in AAA formation protein synthesis was inhibited using an ASO. Hypercholesterolemia was induced in male mice by expressing PCSK9-D377Y and maintained on a Western diet before being infused with AngII (1000 ng/kg/min) for 4 weeks to induce AAA. Mice (n = 15 per group) received subcutaneous injections of either phosphate-buffered saline or HMGB1 ASO (25 mg/kg/day) on days 0 and 3, followed by weekly injections for the remainder of the study. HMGB1 ASO administration significantly attenuated AngII-induced AAA formation in the absence of any changes in blood pressure. CONCLUSIONS: ASO-driven HMGB1 inhibition resulted in a profound attenuation of AngII-induced AAA, highlighting its potential as a therapeutic target for AAAs.