Identification of a pathological feed‐forward loop linking succinate, HIF1α signalling and vascular remodelling in abdominal aortic aneurysm

BACKGROUND: Succinate is a metabolite with roles beyond energy production, including regulation of metabolic pathways, signalling and protein modifications. Abdominal aortic aneurysm (AAA) is a disease characterized by deleterious remodelling of the aortic wall, increasing the risk of rupture and sudden death. Although succinate has been linked to vascular diseases, its regulation within the aorta and potential involvement in AAA remain unclear. AIMS AND RESULTS: In this study, we combined analyses of human plasma and aortic tissue with cell culture experiments to help understand the role of succinate in AAA pathogenesis. Analysis of plasma samples from 461 AAA patients and 189 age-matched controls (67-72 years) from the 'Viborg Vascular Screening Trial' showed significantly increased succinate levels in AAA individuals, approximately 28% higher than in controls. Logistic regression adjusted for cardiovascular risk factors confirmed a strong association (OR = 4.56; 95% CI: 2.57-8.09, highest vs. lowest tertile). Analysis of tissue homogenates confirmed elevated succinate levels in AAA compared to control aortic tissue. Transcriptomic analyses of public AAA datasets indicated that succinate accumulation may result from downregulation of the succinate dehydrogenase complex and upregulation of the gamma-aminobutyric acid shunt pathway, particularly in vascular smooth muscle cells (VSMCs). In cultures, we showed that dedifferentiation increases succinate production, while succinate treatment, in turn, promotes VSMC dedifferentiation in a process involving HIF1α. CONCLUSIONS: Our study proposes succinate as a driver of AAA through a feed-forward loop involving HIF1α signalling and VSMC phenotypic switching. Our work identifies the succinate-HIF1α axis as a promising therapeutic target to disrupt key pathological processes underlying AAA.