Locally Applied Leptin Induces Regional Aortic Wall Degeneration Preceding Aneurysm Formation in Apolipoprotein E–Deficient Mice

Abstract

Objective Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aorta aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process. Methods and Results Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor (ObR), as well as mRNA for matrix metalloproteinases (MMP)-9, and MMP-12. Leptin and ObR antigen were evident in all AAAs, and, leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched non-dilated controls. To simulate in vivo local leptin synthesis, ApoE-/- mice were subjected to a para-visceral peri-aortic application of low-dose leptin. Leptin-treated aortas exhibited decreased TGFβ and increased MMP-9 mRNA levels 5 days after surgery, and ObR mRNA was up-regulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12 and peri-adventitial macrophage clustering. Furthermore, the combination of local peri-aortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size. Conclusions Leptin is locally synthesized in human AAA wall. Para-visceral aortic leptin in ApoE-/- mice induces local medial degeneration, and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

“…The phenotype induced by local application of leptin is similar to AngII‐induced aortic remodeling,14, 18 suggesting that leptin may mediate this phenomenon. To test this hypothesis, apoE −/− mice were infused with AngII for 4 weeks after they received a polylactic co–glycolic acid film containing LepA or no protein that was applied on the surface of the proximal ascending aorta (details under Methods).…”

“…To this end, we combined data from the current model with data from a previous experiment, which included a similar cohort of apoE −/− mice from the same breeding house (n=13) and receiving the same dose AngII infusion for the same duration 14. We observed 45% overall mortality (referred to as premature death prior to the completion of the experiment) in 31 mice treated with AngII alone or AngII with control film applied on the ascending aortic surface.…”

“…AngII infusion in mouse models induces leptin synthesis in arterial wall SMCs and macrophages. Leptin was previously shown to modulate multiple gene expression in the aortic wall 14. In addition, leptin elicits macrophage chemotaxis, and macrophages have been shown infiltrating the arterial media and periadventitial tissue in the AngII‐infusion mouse model.…”

Effects of duodenal-jejunal bypass on structure of diaphragm in western diet obese rats

“…According to Hu et al 11 , moderately obese rats submitted to a high calorie diet have a high concentration of leptin. This hormone enhances the activity of the metalloproteinases MMP-229 29 and the mRNA expression of MMP-9 30 , enzymes responsible for collagen degradation. As the percentage of collagen in the diaphragm muscle was similar in the WD DJB and WD SHAM groups, it is suggested that the continued use of the cafeteria diet and the maintenance of post-DJB body weight maintained the leptin concentration and activity of matrix metalloproteinases high, leading to increased degradation of collagen in relation to its synthesis.…”

Surgical injury induces local and distant adipose tissue browning

“…24 Differences in total RNA or different efficiency of cDNA synthesis among samples were normalized using mouse Hprt1 expression and results expressed as ratio to baseline.…”