Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system has been invoked in the development of both abdominal and thoracic aortic aneurysms. This has been demonstrated experimentally by the chronic subcutaneous infusion of angiotensin II, which consistently leads to development of abdominal aortic aneurysms (AAAs) in mice. Angiotensin II-induced AAAs have highly heterogenous cellular and extracellular matrix characteristics throughout the aorta that change markedly with infusion duration. The mechanistic basis for the reproducible location of AAA development has not been elucidated, but many insights have been provided, especially regarding receptor and inflammatory mechanisms. A recent clinical study provided limited evidence for extrapolating these results to mechanisms of human AAAs. Experimental evidence has also demonstrated that antagonism of angiotensin II type 1 (AT1) receptors prevents ascending aortic aneurysms in a murine model of Marfan's syndrome. A clinical study is currently ongoing to demonstrate the efficacy of AT1 receptor antagonism in humans.
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PMID:The role of the renin-angiotensin system in aortic aneurysmal diseases. 1847 75

A role of ACE I/D polymorphism in the pathogenesis of abdominal aortic aneurysm (AAA) has been demonstrated, possibly due to the effect of angiotensin II on vascular tissue remodelling. Angiotensin II exerts profibrogenic effects through the local induction of TGF-beta. Dysregulated TGF-beta signalling may result from mutations in TGFBR1 and TGFBR2 genes, thus resulting in degenerative changes in the vessel wall. We performed a case-control study in order to investigate the role of TGFBR1 9A6A polymorphism as predisposing factor to AAA per se, and in the presence of ACE DD and AT1R 1166 CC genotypes in 201 AAA patients (mean age+/-S.D., 71.5+/-6.9) referred to the Unit of Vascular Surgery of the University of Florence, compared with 252 healthy controls (mean age+/-S.D., 70.6+/-8.6). A significant difference in genotype distribution and allele frequency between patients and controls was found for ACE, but not for AT1R and TGFBR1 polymorphisms. At univariate analysis a significant association between ACE DD, but not AT1R CC and TGFBR1 6A allele, and the susceptibility to the disease was found [ACE DD OR=1.86 (95% CI 1.26-2.76), p=0.002]. After adjustment for age, gender, traditional cardiovascular risk factors, and CAD, PAD and CVD, ACE DD genotype still affected the susceptibility to AAA [OR=2.13 (95% CI 1.06-4.28), p=0.03], and the contemporary presence of ACE DD genotype and TGFBR1 6A allele, increased the predisposition to the disease [OR=5.09 (95% CI 1.44-18.02), p=0.01]. This study, which demonstrates an interaction between ACE and TGFBR1 genes in predisposing to AAA, may provide further information on the mechanisms contributing to AAA susceptibility, and offer a topic for future larger studies.
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PMID:ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm. 1855 62

Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function and a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. Here we investigated whether the apelin-APJ pathway can directly antagonize vascular disease-related Ang II actions. In ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II-mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II-mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling.
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PMID:Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. 1876 30

Angiotensin (Ang) II exerts direct effects on the arterial wall to influence atherosclerosis and aneurysm development with the induction of vascular inflammation. Therefore, we examined the hypothesis that the inhibition of Ang II would decrease the expansion of abdominal aortic aneurysm (AAA) in a rat model. We used the Ang II receptor blocker (ARB) valsartan to inhibit the effect of Ang II. Additionally, we employed a dosage of valsartan (1 mg/ kg/day) that does not affect blood pressure, to avoid the effect of blood pressure lowering. Notably, progression of elastase-induced AAA was inhibited in rats treated with valsartan (P< or =0.05). To clarify the mechanism, we focused on matrix metalloproteases (MMPs) and inflammatory related factors. Western blot analysis demonstrated that the expression of MMPs was significantly decreased in an AAA model treated with continuous ARB infusion compared to an AAA model treated with vehicle (P< or =0.05), through suppression of nuclear factor kappaB activation (P< or =0.05). Consistently, valsartan significantly inhibited infiltration of macrophages into the aortic wall, accompanied by a reduction of protein expression of intercellular adhesion molecule-1. Importantly, the inhibitory effect of valsartan on MMP-2 and MMP-9 expression was also confirmed using isolated peritoneal macrophages from a rat AAA model. Moreover, treatment with valsartan protected against the destruction of elastic fibers. Overall, the present study demonstrated that treatment with valsartan, significantly prevented the progression of experimental AAA in a rat model. These data suggest that blockade of Ang II has an inhibitory effect on the development of AAA, independent of its antihypertensive effect.
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PMID:Inhibition of experimental abdominal aortic aneurysm in a rat model by the angiotensin receptor blocker valsartan. 1902 Jul 66

Clinical evidence links increased aortic collagen content and stiffness to abdominal aortic aneurysm (AAA) formation. However, the possibility that excess collagen contributes to AAA formation remains untested. We investigated the hypothesis that augmented collagen promotes AAA formation, and employed apoE-null mice expressing collagenase-resistant mutant collagen (Col(R/R)/apoE(-/-)), heterozygote (Col(R/+)/apoE(-/-)), or wild-type collagen (Col(+/+)/apoE(-/-)) infused with angiotensin II to induce AAA. As expected, the aortas of Col(R/R)/apoE(-/-) mice contained more interstitial collagen than those from the other groups. Angiotensin II treatment elicited more AAA formation in Col(R/R)/apoE(-/-) mice than Col(R/+)/apoE(-/-) or Col(+/+)/apoE(-/-) mice. Aortic circumferences correlated positively with collagen content, determined by picrosirius red and Masson trichrome staining. Mechanical testing of aortas of Col(R/R)/apoE(-/-) mice showed increased stiffness and susceptibility to mechanical failure compared to those of Col(+/+)/apoE(-/-) mice. Optical analysis further indicated altered collagen fiber orientation in the adventitia of Col(R/R)/apoE(-/-) mice. These results demonstrate that collagen content regulates aortic biomechanical properties and influences AAA formation.
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PMID:Genetically engineered resistance for MMP collagenases promotes abdominal aortic aneurysm formation in mice infused with angiotensin II. 1915 55

The abdominal aortic aneurysm (AAA) is a common vascular disease. The current clinical criterion for treating AAAs is an increased diameter above a critical value. However, the maximum diameter does not correlate well with aortic rupture, the main cause of death from AAA disease. AAA disease leads to changes in the aortic wall mechanical properties. The pulse-wave velocity (PWV) may indicate such a change. Because of limitations in temporal and spatial resolution, the widely used foot-to-foot method measures the global, instead of regional, PWV between two points at a certain distance in the circulation. However, mechanical properties are nonuniform along the normal and pathological (e.g., the AAA and atherosclerosis) arteries; thus, such changes are typically regional. Pulse-wave imaging (PWI) has been developed by our group to map the pulse-wave propagation along the abdominal aorta in mice in vivo. By using a retrospective electrocardiogram (ECG) gating technique, the radio-frequency (RF) signals over one cardiac cycle were obtained in murine aortas at the extremely high frame rate of 8 kHz and with a field-of-view (FOV) of 12 x 12 mm(2). The velocities of the aortic wall were estimated using an RF-based speckle tracking method. An Angiotensin II (AngII) infusion-based AAA model was used to simulate the human AAA case. Sequences of wall velocity images can noninvasively and quantitatively map the propagation of the pulse wave along the aortic wall. In the normal and sham aortas, the propagation of the pulse wave was relatively uniform along the wall, while in the AngII-treated aortas, the propagation was shown to be nonuniform. There was no significant difference ( p > 0.05) in the PWV between sham (4.67 +/- 1.15 m/s, n=5) and AngII-treated (4.34 +/- 1.48 m/s, n=17) aortas. The correlation coefficient of the linear regression was significantly higher ( p < 0.005) in the sham aortas (0.89 +/- 0.03, n=5 ) than in the AngII-treated ones (0.61 +/- 0.15, n=17). The wall velocities induced by the pulse wave were lower and the pulse wave moved nonuniformly along the AngII-treated aorta ( p < 0.005), with the lowest velocities at the aneurysmal regions. The discrepancy in the regional wall velocity and the nonuniform pulse-wave propagation along the AngII-treated aorta indicated the inhomogeneities in the aortic wall properties, and the reduced wall velocities indicated stiffening of the aneurysmal wall. This novel technique may thus constitute an early detection tool of vascular degeneration as well as serve as a suitable predictor of AAA rupture, complementary to the current clinical screening practice.
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PMID:Pulse wave imaging of normal and aneurysmal abdominal aortas in vivo. 1927 85

Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE-/- mice. Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE-/- and catK-//-apoE-/- mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK-/-//apoE-/- versus apoE-/- mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE-/- mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK-/-//apoE-/- mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK-/-//apoE-/- compared to apoE-/- mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK-//-apoE-/- mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation.
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PMID:Cathepsin K gene disruption does not affect murine aneurysm formation. 1977 91

Leukotriene B(4) (LTB(4)) is a pro-inflammatory lipid mediator generated by the enzymes 5-lipoxygenase (5-LO) and LTA(4)-hydrolase. LTB(4) signals primarily through its G protein-coupled receptor BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. Here we tested the hypothesis that pharmacological inhibition of BLT1 diminishes abdominal aortic aneurysm (AAA) formation, a major complication associated with atherosclerotic vascular disease. Chow-fed Apoe(-/-) mice were treated with a 4-week infusion of Angiotensin II (AngII, 1000 ng/(kg min)) beginning at 10 weeks of age, in a well-established murine AAA model. Administration of the selective BLT1 antagonist CP-105,696 beginning simultaneously with AngII infusion reduced the incidence of AAA formation from 82% to 40% (p<0.05). There was a concordant reduction in maximal aortic diameter from 2.35 mm to 1.56 mm (p<0.05). While administration of the antagonist on day 14 after the onset of AngII infusion diminished lesional macrophage accumulation, it did not significantly alter the size of AAA by day 42. Thus, pharmacological inhibition of BLT1 may ultimately hold clinical promise, but early intervention may be critical.
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PMID:Pharmacological inhibition of BLT1 diminishes early abdominal aneurysm formation. 2003 40

TGF-beta regulates many aspects of cellular performance relevant to tissue morphogenesis and homeostasis. Postnatal perturbation of TGF-beta signaling contributes to the pathogenesis of many disease states, as recently exemplified through the study of Marfan syndrome (MFS), including aortic aneurysm and skeletal muscle myopathy. Heterogeneity in the regulation and consequences of TGF-beta signaling, amplified in the context of disease, has engendered confusion and controversy regarding its utility as a therapeutic target. Three studies recently published in the JCI, including one in this issue, underscore the complexity of this subject. Heydemann and colleagues implicate dimorphic variation in latent TGF-beta-binding protein 4 (LTBP4), a regulator of TGF-beta bioavailability and activation, as a modifier of muscular dystrophy in gamma-sarcoglycan-deficient mice. In contrast to experience with ascending aortic aneurysm in MFS, Wang and colleagues show that systemic abrogation of TGF-beta signaling worsens (rather than attenuates) Ang II-induced abdominal aortic aneurysm progression in mice. Tieu and colleagues define alterations in the regulation of vascular inflammation in the pathogenesis of Ang II-induced aneurysm and dissection in mice, which may help shed some light on this apparent paradox.
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PMID:TGF-beta in the pathogenesis and prevention of disease: a matter of aneurysmic proportions. 2010 Oct 93

Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-beta activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-beta in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-beta activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II-induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-gamma, IL-4, IL-6, or TNF-alpha signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-beta activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-beta neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-beta in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.
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PMID:TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. 2010 Oct 91


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