AT1-receptor blockade attenuates outward aortic remodeling associated with diet-induced obesity in mice

Friedrich Krueger, Kai Kappert, Anna Foryst-Ludwig, Frederike Kramer, Markus Clemenz, Aleksandra Grzesiak, Manuela Sommerfeld, Jan Paul Frese, Andreas Greiner, Ulrich Kintscher, Thomas Unger, Elena Kaschina*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

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 (3mg/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 alpha(TNF-alpha) and interleukin-1 beta (IL-1 beta) 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-alpha was abrogated by telmisartan. Adventitial proteolytic and inflammatory factors were also examined in samples from human abdominal aneurysms. The expression of TNF-alpha, IL-1 beta, and MMP-9 was higher in the adventitial fat of diseased vessels compared with healthy tissues. Finally, adipocytes treated with TNF-alpha 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.

Original languageEnglish
Pages (from-to)1989-2005
Number of pages17
JournalClinical Science
Volume131
Issue number15
DOIs
Publication statusPublished - 1 Aug 2017

Keywords

  • MATRIX METALLOPROTEINASES
  • ADIPOSE-TISSUE
  • CARDIOVASCULAR-DISEASE
  • RECEPTOR BLOCKERS
  • BLOOD-PRESSURE
  • MOUSE MODEL
  • ANEURYSM
  • EXPRESSION
  • INFLAMMATION
  • TELMISARTAN

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