AT1-receptor blockade attenuates outward aortic remodeling associated with diet-induced obesity in mice.
The renin-angiotensin system (RAS) and obesity have been implicated in vascular outward remodeling, including aneurysms, but the precise mechanisms are not yet understood. We investigated the effect of the angiotensin receptor type 1 (AT1-receptor) antagonist telmisartan on aortic outward remodeling in a diet-induced obesity model in mice. C57/Black6J mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 14 weeks. One group of HFD mice was additionally exposed to telmisartan (3 mg/kg per day) for the last 4 weeks. HFD led to aortic outward remodeling, characterized by increased proteolysis, along with structural changes, such as fragmentation of elastic fibers and decreased elastin content. Vascular damage was associated with up-regulation of matrix metalloproteinase (MMP)-2 (MMP-2), MMP-3, MMP-12, cathepsin D, and cathepsin B. HFD aortae exhibited an enhanced inflammatory status, characterized by tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) colocalized with adipocytes in the adventitia. HFD resulted in a significant increase in aortic dimensions, evident by ultrasound measurements. Telmisartan abolished aortic dilatation and preserved elastin content. HFD induced enhanced expression of aortic MMP-2, MMP-9, and TNF-α was abrogated by telmisartan. Adventitial proteolytic and inflammatory factors were also examined in samples from human abdominal aneurysms. The expression of TNF-α, IL-1β, and MMP-9 was higher in the adventitial fat of diseased vessels compared with healthy tissues. Finally, adipocytes treated with TNF-α showed enhanced MMP-2, MMP-3, and cathepsin D, which was prevented by telmisartan. Taken together, HFD in mice induced aortic dilatation with up-regulation of matrix degrading and inflammatory pathways similar to those seen in human aortic aneurysmatic tissue. The HFD-induced vascular pathology was reduced by AT1-receptor antagonist telmisartan.
['Krueger|Friedrich|F|', 'Kappert|Kai|K|', 'Foryst-Ludwig|Anna|A|', 'Kramer|Frederike|F|', 'Clemenz|Markus|M|', 'Grzesiak|Aleksandra|A|', 'Sommerfeld|Manuela|M|', 'Frese|Jan Paul|JP|', 'Greiner|Andreas|A|', 'Kintscher|Ulrich|U|', 'Unger|Thomas|T|', 'Kaschina|Elena|E|']
D047228:Angiotensin II Type 1 Receptor Blockers D000818:Animals D001011:Aorta D059305:Diet, High-Fat D006801:Humans D053508:Matrix Metalloproteinase 12 D020778:Matrix Metalloproteinase 2 D019278:Matrix Metalloproteinase 3 D051379:Mice D008810:Mice, Inbred C57BL D009765:Obesity D044140:Receptor, Angiotensin, Type 1 D014409:Tumor Necrosis Factor-alpha D014652:Vascular Diseases D066253:Vascular Remodeling
angiotensin high-fat diet MMP abdominal aortic aneurysm vascular remodeling