Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II-Induced Abdominal Aortic Aneurysms.
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ABSTRACT: Abdominal 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.Female 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.Female 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.An 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.
<h4>Background</h4>Abdominal 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 ...[more]
Project description:Abdominal aortic aneurysms (AAAs) are a prevalent and deadly human pathology with strong sexual dimorphism. Research demonstrates that sex hormones influence, but do not fully explain, male versus female AAA pathology. 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, for the first time, we defined the effect of female (XX) versus male (XY) chromosome complement on AAA formation and rupture in phenotypically female mice using an established murine model. Abdominal aortas from female mice bearing the XY chromosome selectively expressed Y chromosome genes, while genes known to escape X-inactivation were higher in XX females. The majority of gene differences in XY females fell within inflammatory pathways. When XY females were infused with AngII, AAA incidences doubled and aneurysms ruptured. AAAs from XY females exhibited significant inflammation. Moreover, infusion of AngII to XY females augmented aortic activity of matrix metalloproteinases. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to XX females. These results demonstrate that an XY sex chromosome complement profoundly influences aortic gene expression profiles and promotes AAA severity.
Project description:Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure.Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II-induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab(-/-)/ApoE(-/-)) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59(ICAM-2+/-)/ApoE(-/-)) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK-alpha/beta, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor-kappaB signaling pathways.Together, these results defined the protective role of CD59 and shed light on the important pathogenic role of the membrane attack complex in abdominal aortic aneurysm.
Project description:ObjectiveThe goal of this study was to investigate the role of complement cascade genes in the pathobiology of human abdominal aortic aneurysms (AAAs).Methods and resultsResults of a genome-wide microarray expression profiling revealed 3274 differentially expressed genes between aneurysmal and control aortic tissue. Interestingly, 13 genes in the complement cascade were significantly differentially expressed between AAA and the controls. In silico analysis of the promoters of the 13 complement cascade genes showed enrichment for transcription factor binding sites for signal transducer and activator of transcription (STAT)5A. Chromatin-immunoprecipitation experiments demonstrated binding of transcription factor STAT5A to the promoters of the majority of the complement cascade genes. Immunohistochemical analysis showed strong staining for C2 in AAA tissues.ConclusionsThese results provide strong evidence that the complement cascade plays a role in human AAA. Based on our microarray studies, the pathway is activated in AAA, particularly via the lectin and classical pathways. The overrepresented binding sites of transcription factor STAT5A in the complement cascade gene promoters suggest a role for STAT5A in the coordinated regulation of complement cascade gene expression.
Project description:Objective-Aortic pathologies exhibit sexual dimorphism, with aneurysms in the ascending, thoracic and abdominal aorta (AAA) exhibiting higher prevalence in males. Despite lower incidence of aortic vascular disease in women, aneurysms progress rapidly. Mechanisms for these sex differences are unclear. We defined the role of sex chromosome complement and testosterone in regional development and progression of angiotensin II (AngII)-induced vascular pathologies. Approach and Results-We used transgenic male mice expressing Sry on an autosome to create low density lipoprotein receptor (Ldlr) deficient male mice with an XY or XX sex chromosome complement. Subjects were then sham operated or orcheictomized. Transcriptional profiling on abdominal aortas from XY or XX males demonstrated1746 genes influenced by sex chromosomes, sex hormones, or an interaction. A second cohort of animals was then infused with AngII for 28 days. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, while XX males developed discrete AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males, but not XX males exhibited adventitial thickening. We infused male XY and XX mice with saline or AngII and quantified mRNA abundance of key genes in thoracic versus abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in AAA aortic wall thickening in XY males with diffuse aortic pathology, while XX males had dilated focal AAAs. Conclusions-An XY sex chromosome complement mediates diffuse aortic pathology, while an XX sex chromosome complement contributes to discrete AngII-induced AAAs.
Project description:ObjectiveAortic pathologies exhibit sexual dimorphism, with aneurysms in both the thoracic and abdominal aorta (ie, abdominal aortic aneurysm [AAA]) exhibiting higher male prevalence. Women have lower prevalence of aneurysms, but when they occur, aneurysms progress rapidly. To define mechanisms for these sex differences, we determined the role of sex chromosome complement and testosterone on the location and progression of angiotensin II (AngII)-induced aortic pathologies.Approach and resultsWe used transgenic male mice expressing Sry (sex-determining region Y) on an autosome to create Ldlr (low-density lipoprotein receptor)-deficient male mice with an XY or XX sex chromosome complement. Transcriptional profiling was performed on abdominal aortas from XY or XX males, demonstrating 1746 genes influenced by sex chromosomes or sex hormones. Males (XY or XX) were either sham-operated or orchiectomized before AngII infusions. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, whereas XX males developed focal AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males exhibited adventitial thickening that was not present in XX males. We infused male XY and XX mice with either saline or AngII and quantified mRNA abundance of key genes in both thoracic and abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in aortic wall thickening of AAAs from XY males, whereas XX males had dilated focal AAAs.ConclusionsAn XY sex chromosome complement mediates diffuse aortic pathology, whereas an XX sex chromosome complement contributes to focal AngII-induced AAAs.
Project description:BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture.MethodsExperimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE - / - mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).ResultsThe size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate.ConclusionPemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.
Project description:Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (AngII) to form angiotensin-(1-7) (Ang-(1-7)), which generally opposes effects of AngII. AngII infusion into hypercholesterolemic male mice induces formation of abdominal aortic aneurysms (AAAs). This study tests the hypothesis that deficiency of ACE2 promotes AngII-induced AAAs, whereas ACE2 activation suppresses aneurysm formation.ACE2 protein was detectable by immunostaining in mice and human AAAs. Whole-body deficiency of ACE2 significantly increased aortic lumen diameters and external diameters of suprarenal aortas from AngII-infused mice. Conversely, ACE2 deficiency in bone marrow-derived cells had no effect on AngII-induced AAAs. In contrast to AngII-induced AAAs, ACE2 deficiency had no significant effect on external aortic diameters of elastase-induced AAAs. Because ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined whether ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazene aceturate (30 mg/kg per day) to Ldlr(-/-) mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of diminazene aceturate significantly reduced total sera cholesterol and very low-density lipoprotein-cholesterol concentrations. Notably, diminazene aceturate significantly decreased aortic lumen diameters and aortic external diameters of AngII-infused mice resulting in a marked reduction in AAA incidence (from 73% to 29%). None of these effects of diminazene aceturate were observed in the Ace2(-/y) mice.These results demonstrate that ACE2 exerts a modulatory role in AngII-induced AAA formation, and that therapeutic stimulation of ACE2 could be a benefit to reduce AAA expansion and rupture in patients with an activated renin-angiotensin system.
Project description:Background and purposeTo test the hypothesis that angiotensin-(1-7) [Ang-(1-7)] may attenuate abdominal aortic aneurysm (AAA) via inhibiting vascular inflammation, extracellular matrix degradation, and smooth muscle cell (SMC) apoptosis, an animal model of AAA was established by angiotensin II (Ang II) infusion to apolipoprotein E-knockout (ApoE-/- ) mice.Experimental approachAll mice and cultured SMCs or macrophages were divided into control, Ang II-treated, Ang II + Ang-(1-7)-treated, Ang II + Ang-(1-7) + A779-treated and Ang II + Ang-(1-7) + PD123319-treated groups respectively. In vivo, aortic mechanics and serum lipids were assessed. Ex vivo, AAA were examined by histology, immunohistochemistry and zymography. Cultured cells were analysed by RT-PCR, western blots and TUNEL assays.Key resultsIn vivo, Ang-(1-7) reduced the incidence and severity of AAA induced by Ang II infusion, by inhibiting macrophage infiltration, attenuating expression of IL-6, TNF-α, CCL2 and MMP2, and decreasing SMC apoptosis in abdominal aortic tissues. Addition of A779 or PD123319 reversed Ang-(1-7)-mediated beneficial effects on AAA. In vitro, Ang-(1-7) decreased expression of mRNA for IL-6, TNF-α, and CCL2 induced by Ang II in macrophages. In addition, Ang-(1-7) suppressed apoptosis and MMP2 expression and activity in Ang II-treated SMCs. These effects were accompanied by inhibition of the ERK1/2 signalling pathways via Ang-(1-7) stimulation of Mas and AT2 receptors.Conclusion and implicationsAng-(1-7) treatment attenuated Ang II-induced AAA via inhibiting vascular inflammation, extracellular matrix degradation, and SMC apoptosis. Ang-(1-7) may provide a novel and promising approach to the prevention and treatment of AAA.
Project description:Asthma and abdominal aortic aneurysms (AAA) both involve inflammation. Patients with asthma have an increased risk of developing AAA or experiencing aortic rupture. This study tests the development of one disease on the progression of the other.Ovalbumin sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth muscle cell loss, cell proliferation, and angiogenesis in AAA lesions. ALI also increased plasma IgE, reduced plasma interleukin-5, and increased bronchioalveolar total inflammatory cell and eosinophil accumulation. Intraperitoneal administration of an anti-IgE antibody suppressed AAA lesion formation and reduced lesion inflammation, plasma IgE, and bronchioalveolar inflammation. Pre-establishment of ALI also increased AAA lesion size, lesion accumulation of macrophages and mast cells, media smooth muscle cell loss, and plasma IgE, reduced plasma interleukin-5, interleukin-13, and transforming growth factor-?, and increased bronchioalveolar inflammation. Consequent production of ALI also doubled lesion size of pre-established AAA and increased lesion mast cell and T-cell accumulation, media smooth muscle cell loss, lesion cell proliferation and apoptosis, plasma IgE, and bronchioalveolar inflammation. In periaortic CaCl2 injury-induced AAA in mice, production of ALI also increased AAA formation, lesion inflammation, plasma IgE, and bronchioalveolar inflammatory cell accumulation.This study suggests a pathological link between airway allergic disease and AAA. Production of one disease aggravates the progression of the other.
Project description:BackgroundThis study determined whether relaxin or matrix metalloproteinase (MMP)-9 influences angiotensin II (AngII)-induced abdominal aortic aneurysms (AAA).Methods and Results:Male C57BL/6 or apolipoprotein E-/-mice were infused with AngII with or without relaxin. Relaxin did not influence AngII-induced AAA in either mouse strain. Infusion of AngII reduced, but relaxin increased, MMP-9 mRNA in macrophages. We then determined the effects of MMP-9 deficiency on AAA in apolipoprotein E-/-mice. MMP-9 deficiency led to AAA formation in the absence of AngII, and augmented AngII-induced aortic rupture and AAA incidence.ConclusionsMMP-9 deficiency augmented AngII-induced AAA.
