Dataset Information

Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure.

ABSTRACT:

Objective

Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E(-/-) mice.

Approach

A cohort of mice underwent a 4-week pump-mediated infusion of saline (n?=?23) or 1500 ng/kg/min of Ang II (n?=?85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.

Results

The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (-0.234, p?=?0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p?=?0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (?) (SBP, p?=?0.66; DBP, p?=?0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p?=?0.86).

Conclusions

These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.

SUBMITTER: Prins PA

PROVIDER: S-EPMC3900396 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure.

Prins Petra A PA Hill Michael F MF Airey David D Nwosu Sam S Perati Prudhvidhar R PR Tavori Hagai H F Linton Macrae M Kon Valentina V Fazio Sergio S Sampson Uchechukwu K UK

PloS one 20140123 1

<h4>Objective</h4>Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E(-/-) mice.<h4>Approach</h4>A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for he ...[more]

PMID: 24465413

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Project description:BACKGROUNDAbdominal aortic aneurysms (AAAs) are a deadly pathology with strong sexual dimorphism. Similar to humans, female mice exhibit far lower incidences of angiotensin II-induced AAAs than males. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, we defined the effect of female (XX) versus male (XY) sex chromosome complement on angiotensin II-induced AAA formation and rupture in phenotypically female mice.METHODSFemale low-density lipoprotein receptor (Ldlr) deficient mice with an XX or XY sex chromosome complement were infused with angiotensin II for 28 days to induce AAAs. Abdominal aortic lumen diameters were quantified by ultrasound, whereas AAA diameters were quantified at study end point. DNA microarrays were performed on abdominal aortas. To mimic males, female mice were administered a single dose of testosterone as neonates or as adults before angiotensin II infusions.RESULTSFemale Ldlr-/- deficient mice with an XX and XY sex chromosome complement had similar sex organ weights and low serum testosterone concentrations. Abdominal aortas from female XY mice selectively expressed Y chromosome genes, whereas genes known to escape X inactivation were higher in XX females. The majority of aortic gene differences in XY versus XX females fell within inflammatory pathways. AAA incidences doubled and aneurysms ruptured in XY females. AAAs from XY females exhibited inflammation, and plasma interleukin-1? concentrations were increased in XY females. Moreover, aortas from XY females had augmented matrix metalloproteinase activity and increased oxidative stress. Last, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY in comparison with XX adult females.CONCLUSIONSAn XY sex chromosome complement in phenotypic females profoundly influenced aortic gene expression profiles and promoted AAA severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. Mechanisms for augmented AAA severity in XY females include increased inflammation, augmented matrix metalloproteineases, and oxidative stress. Our results demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of AAAs. Sex chromosome genes may serve as novel targets for sex-specific AAA therapeutics.

Dataset Information

Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure.

Objective

Approach

Results

Conclusions

Publications

Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure.

Similar Datasets

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