Tirzepatide, a dual GIP/GLP-1 receptor agonist, attenuates endothelial dysfunction and angiotensin II-induced abdominal aortic aneurysm in ApoE-/- mice

Endothelial dysfunction is a critical initiating event in abdominal aortic aneurysm (AAA), a condition posing a high risk of a fatal rupture. Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists have emerged as potent treatments for diabetes and obesity, with clinical evidence suggesting broader cardiovascular benefits. However, the direct impact of tirzepatide (dual GLP-1R/GIPR agonist) on endothelial dysfunction and AAA pathogenesis remains poorly understood. We investigated the effects of dual GLP-1R/GIPR agonism on endothelial dysfunction and AAA development. We employed parallel-plate flow chamber assays to evaluate the effects of tirzepatide on TNFα-induced leukocyte-endothelium interactions. Expression of GLP-1R, GIPR, adhesion molecules (VCAM-1 and ICAM-1), and NF-κB activation was quantified using immunofluorescence and western blotting. The in vivo efficacy of tirzepatide was assessed using an angiotensin-II-infused apoE^-/- mouse model of AAA. GLP-1R and GIPR were expressed in human endothelial cells and murine suprarenal aortas. Tirzepatide significantly attenuated TNFα-induced leukocyte-endothelium interactions, downregulated VCAM-1/ICAM-1/CX₃CL1 expression, and inhibited the mRNA expression and generation of MCP-1 and RANTES. Mechanistically, these effects were driven by the suppression of NF-κB activation. Chronic subcutaneous administration of tirzepatide over 28 days significantly limited suprarenal aortic expansion and reduced AAA incidence in Ang-II-infused mice. This vasoprotective effect was characterized by preserved elastin integrity, reduced neovessel formation, and diminished macrophage accumulation within the aneurysmal wall. Dual GLP-1R/GIPR agonism mitigates endothelial dysfunction and suppresses inflammatory pathways driving AAA progression. These findings position tirzepatide as a promising therapeutic strategy for the prevention of vascular remodeling and AAA development.

Abdominal aortic aneurysm; Angiotensin-II; Endothelial dysfunction, tirzepatide; GIP receptor; GLP-1 receptor; Inflammation.