Antisense oligonucleotide inhibition of HMGB1 attenuates angiotensin II-induced abdominal aortic aneurysms

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.