Dataset Information

Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice.

ABSTRACT: Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process.Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE(-/-) mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-? and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated 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 periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size.Leptin is locally synthesized in human AAA wall. Paravisceral 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.

SUBMITTER: Tao M

PROVIDER: S-EPMC3645930 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice.

Tao Ming M Yu Peng P Nguyen Binh T BT Mizrahi Boaz B Savion Naphtali N Kolodgie Frank D FD Virmani Renu R Hao Shuai S Ozaki C Keith CK Schneiderman Jacob J

Arteriosclerosis, thrombosis, and vascular biology 20121206 2

<h4>Objective</h4>Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process.<h4>Methods and results</h4>Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP- ...[more]

PMID: 23220275

Similar Datasets

Project description:The cleavage of osteopontin (OPN) by thrombin results in an N-terminal fragment (OPN-N), which exposes a cryptic integrin-binding motif that promotes the adherence of cells, and plays a proinflammatory role. However, the effect of OPN-N on abdominal aortic aneurysm (AAA) remains unknown. The aim of this study was to investigate the expression of OPN-N in aortic tissue samples obtained from patients, who underwent acute aortic dissection (AD), and normal aorta, effect of OPN-N on angiotensin (Ang) II-induced AAA in mice, and relationship between OPN-N and pyroptosis-related inflammatory factors in vitro. Hematoxylin and eosin staining was conducted to detect histological changes. Next, we detected the expression of the OPN-N protein. Additionally, ApoE-/- mice were divided into four groups: control, control + M5Ab (to block the OPN-N function in mice), Ang II, and Ang II + M5Ab. All mice were euthanized after a 28-day infusion and whole aortas, including thoracic and abdominal aortas, were collected for morphological and histological analysis of the AAA. The OPN-N protein expression was higher in patients with AD than in normal individuals, while histological changes in the aortas of Ang II mice were suppressed in Ang II + M5Ab mice. The expression of OPN-N, NOD-, LRR-, and pyrin domain-containing protein 3, pro-Caspase-1, ASC, Gasdermin-d, interleukin (IL)-18, IL-1β, matrix metalloproteinase (MMP) 2, and MMP9 was lower in the Ang II + M5Ab group than in the Ang II group. The gene expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α was suppressed in the aortic tissues of the Ang II + M5Ab group compared with the Ang II group. Moreover, the expression of α-smooth muscle actin was lower in the Ang II group than in the Ang II + M5Ab group. In vitro results showed that the increase in the expression of pyroptosis-related inflammatory factors induced by OPN was mediated through the nuclear factor (NF)-κB pathway. In conclusion, OPN-N promotes AAA by increasing the expression of pyroptosis-related inflammatory factors through the NF-κB pathway, inflammation, and extracellular matrix degradation. These results highlight the potential of OPN-N as a new therapeutic target to prevent AAA expansion.

Project description:Background: The circle of Willis is a network of arteries allowing blood supply to the brain. Bulging of these arteries leads to formation of intracranial aneurysm (IA). Subarachnoid hemorrhage (SAH) due to IA rupture is among the leading causes of disability in the western world. The formation and rupture of IAs is a complex pathological process not completely understood. In the present study, we have precisely measured aneurysmal wall thickness and its uniformity on histological sections and investigated for associations between IA wall thickness/uniformity and commonly admitted risk factors for IA rupture. Methods: Fifty-five aneurysm domes were obtained at the Geneva University Hospitals during microsurgery after clipping of the IA neck. Samples were embedded in paraffin, sectioned and stained with hematoxylin-eosin to measure IA wall thickness. The mean, minimum, and maximum wall thickness as well as thickness uniformity was measured for each IA. Clinical data related to IA characteristics (ruptured or unruptured, vascular location, maximum dome diameter, neck size, bottleneck factor, aspect and morphology), and patient characteristics [age, smoking, hypertension, sex, ethnicity, previous SAH, positive family history for IA/SAH, presence of multiple IAs and diagnosis of polycystic kidney disease (PKD)] were collected. Results: We found positive correlations between maximum dome diameter or neck size and IA wall thickness and thickness uniformity. PKD patients had thinner IA walls. No associations were found between smoking, hypertension, sex, IA multiplicity, rupture status or vascular location, and IA wall thickness. No correlation was found between patient age and IA wall thickness. The group of IAs with non-uniform wall thickness contained more ruptured IAs, women and patients harboring multiple IAs. Finally, PHASES and ELAPSS scores were positively correlated with higher IA wall heterogeneity. Conclusion: Among our patient and aneurysm characteristics of interest, maximum dome diameter, neck size and PKD were the three factors having the most significant impact on IA wall thickness and thickness uniformity. Moreover, wall thickness heterogeneity was more observed in ruptured IAs, in women and in patients with multiple IAs. Advanced medical imaging allowing in vivo measurement of IA wall thickness would certainly improve personalized management of the disease and patient care.

Dataset Information

Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice.

Publications

Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets