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AT1-receptor blockade attenuates outward aortic remodeling associated with diet-induced obesity in mice
Friedrich Krueger1, Kai Kappert2,3, Anna Foryst-Ludwig1,3
1Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin; and Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research (CCR), Germany.
Abstract:
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.
Insights
Diet-induced obesity promotes aortic outward remodeling and inflammation in mice. Telmisartan, an AT1-receptor antagonist, mitigated these effects, suggesting a therapeutic target for vascular disease.
Area of Science:
- Cardiovascular Biology
- Obesity Research
- Pharmacology
Background:
- The renin-angiotensin system (RAS) and obesity are linked to vascular outward remodeling, including aneurysms, but mechanisms remain unclear.
- Diet-induced obesity models offer insights into vascular pathologies.
- Angiotensin receptor type 1 (AT1-receptor) antagonists are potential therapeutic agents.
Purpose of the Study:
- To investigate the impact of telmisartan, an AT1-receptor antagonist, on diet-induced obesity-related aortic outward remodeling in mice.
- To elucidate the molecular mechanisms underlying obesity-associated vascular damage and inflammation.
- To compare findings in a mouse model with human aortic aneurysm tissues.
Main Methods:
- Mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 14 weeks, with some HFD mice receiving telmisartan.
- Aortic dimensions were assessed using ultrasound.
- Proteolytic enzymes (MMPs, cathepsins) and inflammatory markers (TNF-α, IL-1β) were quantified.
- Human abdominal aneurysm tissues were analyzed for similar markers.
- In vitro studies examined adipocyte responses to TNF-α.
Main Results:
- HFD induced aortic outward remodeling, characterized by increased proteolysis (MMP-2, MMP-3, MMP-12, cathepsin D, cathepsin B) and elastin degradation.
- HFD aortae showed enhanced inflammation (TNF-α, IL-1β) in adventitial adipocytes, leading to increased aortic dimensions.
- Telmisartan treatment prevented aortic dilatation, preserved elastin content, and reduced MMP-2, MMP-9, and TNF-α expression.
- Human aneurysmal tissues exhibited elevated TNF-α, IL-1β, and MMP-9 in adventitial fat.
- TNF-α stimulation of adipocytes increased MMPs and cathepsins, effects blocked by telmisartan.
Conclusions:
- Diet-induced obesity in mice causes aortic dilatation via matrix-degrading and inflammatory pathways, mirroring human aortic aneurysms.
- AT1-receptor antagonism with telmisartan effectively reduces HFD-induced aortic pathology.
- Targeting the AT1-receptor may be a viable strategy for preventing or treating obesity-related vascular diseases.
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