Asxl1-mutant clonal hematopoiesis aggravates abdominal aortic aneurysm: mechanistic insights and therapeutic implications

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a driver of the progression of various cardiovascular diseases, including heart failure, atherosclerosis, and thrombosis via inflammatory pathways. Although CHIP is recognized as a factor contributing to worse prognosis in cardiovascular disease, its underlying molecular pathophysiology remains incompletely understood, hampering the development of therapeutic strategies to effectively attenuate its pathogenic effects. Aortic aneurysm can progress to a life-threatening condition, with surgical or endovascular intervention as the only definitive treatments. Clarifying the association between aortic aneurysm and CHIP, along with their underlying molecular mechanisms, could lead to effective therapeutic strategies. Purpose This study investigates the role of ASXL1-mutated CHIP in abdominal aortic aneurysm (AAA) progression and explores potential therapeutic interventions. Methods Eight- to ten-week-old ApoE knock-out mice were irradiated, followed by bone marrow transplantation from Asxl1-mutant (Asxl1-MT) mice to establish an Asxl1-MT CHIP model. AAA was induced by continuous angiotensin II infusion (1,900 ng/kg/min) for four weeks. Abdominal aortic diameter was measured by ultrasound at 2 and 4 weeks. Vascular structure, inflammatory cell infiltration, and inflammatory cytokine expression were analyzed using histology, flow cytometry, qPCR, and RNA sequencing. ELISA was performed to measure IL-1β levels in the supernatant of bone marrow-derived macrophages (BMDM) stimulated with LPS and nigericin to assess NLRP3 inflammasome. Colchicine (0.1 mg/kg/day) was administered continuously for four weeks, and its impact on AAA progression was evaluated. Results Asxl1-MT CHIP mice exhibited significantly accelerated aneurysm formation and increased the probability of dissection, characterized by enhanced infiltration of MHC class II+ CCR2+ macrophages and elevated IL-1β and MMP-9 expression. RNA sequencing from macrophages revealed upregulation of genes related to cell activation and cytokine production. ELISA confirmed increased IL-1β secretion in Asxl1-MT BMDM after NLRP3 inflammasome activation. Colchicine treatment significantly reduced aneurysm severity as well as the development of dissection, suppressed macrophage recruitment, and downregulated IL-1β and MMP-9 expression. ELISA showed colchicine suppressed IL-1β secretion in BMDM. Conclusion Asxl1-mutated CHIP accelerates aortic aneurysm progression via inflammatory mechanisms. Colchicine effectively mitigates aneurysm severity by inhibiting NLRP3 inflammasome activation and inflammatory macrophage infiltration. These findings highlight colchicine as a promising therapeutic strategy for CHIP-associated AAA, warranting further clinical investigation.Graphical Abstract