Regression Of Abdominal Aortic Aneurysm Research Articles

Progression and Regression of Abdominal Aortic Aneurysms in Mice.

Abdominal aortic aneurysm (AAA) is a significant medical problem with a high mortality rate. Nevertheless, the underlying mechanism for the progression and regression of AAA is unknown. Experimental model of AAA was first created by porcine pancreatic elastase incubation around the infrarenal aorta of C57BL/6 mice. Then, AAA progression and regression were evaluated based on the diameter and volume of AAA. The aortas were harvested for hematoxylin-eosin staining (HE), orcein staining, sirius red staining, immunofluorescence analysis and perls' prussian blue staining at the indicated time point. Finally, β-aminopropionitrile monofumarate (BAPN) was used to explore the underlying mechanism of the regression of AAA. When we extended the observation period to 100 days, we not only observed an increase in the AAA diameter and volume in the early stage, but also a decrease in the late stage. Consistent with AAA diameter and volume, the aortic thickness showed the same tendency based on HE staining. The elastin and collagen content first degraded and then regenerated, which corresponds to the early deterioration and late regression of AAA. Then, endogenous up-regulation of lysyl oxidase (LOX) was detected, accompanying the regression of AAA, as detected by an immunofluorescent assay. BAPN and LOX inhibitor considerably inhibited the regression of AAA, paralleling the degradation of elastin lamella and collagen. Taken together, we tentatively conclude that endogenous re-generation of LOX played an influential role in the regression of AAA. Therefore, regulatory factors on the generation of LOX exhibit promising therapeutic potential against AAA.

Molecular Pharmacological Approaches for Treating Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is considered to be a potent life-threatening disorder in elderly individuals. Although many patients with a small AAA are detected during routine abdominal screening, there is no effective therapeutic option to prevent the progression or regression of AAA in the clinical setting. Recent advances in molecular biology have led to the identification of several important molecules, including microRNA and transcription factor, in the process of AAA formation. Regulation of these factors using nucleic acid drugs is expected to be a novel therapeutic option for AAA. Nucleic acid drugs can bind to target factors, mRNA, microRNA, and transcription factors in a sequence-specific fashion, resulting in a loss of function of the target molecule at the transcriptional or posttranscriptional level. Of note, inhibition of a transcription factor using a decoy strategy effectively suppresses experimental AAA formation, by regulating the expression of several genes associated with the disease progression. This review focuses on recent advances in molecular therapy of using nucleic acid drugs to treat AAA.

Evaluating Smooth Muscle Cells from CaCl2-Induced Rat Aortal Expansions as a Surrogate Culture Model for Study of Elastogenic Induction of Human Aneurysmal Cells

Regression of abdominal aortic aneurysms (AAAs) via regeneration of new elastic matrix is constrained by poor elastin synthesis by adult vascular cells and absence of methods to stimulate the same. We recently showed hyaluronan oligomers (HA-o) and TGF-β1 (termed elastogenic factors) to enhance elastin synthesis and matrix formation by healthy rat aortic smooth muscle cells (RASMCs). We also determined that these factors could likewise elastogenically induce aneurysmal RASMCs isolated from periadventitial CaCl(2)-injury induced rat AAAs (aRASMCs). However, the factor doses should be increased for these diseased cell types, as even when induced, elastic matrix amounts are roughly one order of magnitude lower than those produced by healthy RASMCs. We presently investigate the dose-specific elastogenic effects of HA-o (0-20 μg/mL) and TGF-β1 (0-10 ng/mL) factors on aRASMCs and compare their phenotype and elastogenic responses to those of human AAA-derived SMCs (aHASMCs); we seek to determine whether aRASMCs are appropriate surrogate cell types to study in the context of inducing elastic matrix regeneration within human AAAs. The periadventitial CaCl(2)-injury model of AAAs exhibits many of the pathological characteristics of human AAAs, including similarities in terms of decreased SMC contractile activity, enhanced proliferation, and reduced elastogenic capacity of aneurysmal SMCs (relative to healthy SMCs) when isolated and expanded in culture. Both aRASMCs and aHASMCs can be elastogenically stimulated by HA-o and TGF-β1 and show broadly similar trends in their dose-specific responses to these factors. However, compared with aHASMCs, aRASMCs appear to be far less elastogenically inducible. This may be due to differences in maturity of the AAAs studied, with the CaCl(2)-injury induced aortal expansion barely qualifying as an aneurysm and the human AAA representing a more well-developed condition. Further study of SMCs from stage-matched CaCl(2)-injury induced rat aortal expansions and human AAAs will be necessary to more rigorously evaluate their basal and induced elastogenic responses.

Quantitative Estimates of the Variability of In Vivo Sonographic Measurements of the Mouse Aorta for Studies of Abdominal Aortic Aneurysms and Related Arterial Diseases

Burgeoning interest in reducing the morbidity and mortality associated with abdominal aortic aneurysms (AAAs) has led to experimental strategies to elucidate the disease process and attain pharmacologic regression using the apolipoprotein E(-/-) (ApoE(-/-)) mouse model of angiotensin-induced AAAs and in vivo sonography. However, the variability of in vivo sonographic measurements of the mouse aorta has not been established. Thus, our purpose was to determine quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta as a guide for the design and assessment of studies focused on regression of AAAs and related arterial diseases. We used Bland-Altman, locally weighted scatterplot-smoothing regression, and resampling (bootstrapping) methods for variability analyses of multiple in vivo short- and long-axis sonographic measurements of ApoE(-/-) mouse aortas. We measured distinct aortic sites in vivo at the baseline and after angiotensin-induced AAAs and ex vivo using digital calipers. We analyzed 236 data points from 10 male mice (14 weeks old; mean weight ± SD, 29.7 ± 1.6 g). Overall intramouse differences between short- and long-axis and in vivo and ex vivo measurements were 0.038 (95% confidence interval [CI], 0.031-0.046) and 0.085 (95% CI, 0.062-0.109) mm, respectively. Intermouse differences in short-axis measurements were 0.047 (95% CI, 0.042-0.053), 0.049 (95% CI, 0.044-0.055), and 0.039 (95% CI, 0.036-0.042) mm for infrarenal, suprarenal, and thoracic measurements, respectively; differences in long-axis measurements were 0.054 (95% CI, 0.044-0.064), 0.029 (95% CI, 0.024-0.034), and 0.046 (95% CI, 0.037-0.054) mm. Bland-Altman and locally weighted scatterplot-smoothing analyses showed excellent agreement between measures with no variation in discrepancies vis-à-vis the target measurement. These data establish previously undefined estimates of measurement variability relevant for in vivo sonographic studies of AAA regression in a commonly studied mouse model.

Abstract 5539: Tenascin-c Has a Protective Role During the Development of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is an important healthcare problem for which non-surgical treatment is not available. Recently we reported that c-Jun N-terminal kinase-targeted pharmacotherapy can cause the regression of AAA by regulating inflammation and abnormal metabolism of extracellular matrix (ECM). To realize the pharmacotherapy, it is essential to develop the therapeutic biomarker that is involved in the pathogenesis and reflects the disease activity of AAA. We previously reported that tenascin-C (TN-C), an ECM protein, is an appropriate biomarker and can be used for the bioimaging of the inflammatory sites in several inflammatory diseases such as myocarditis. In this study, we tested if TN-C is a suitable biomarker for AAA. The tissue expression of TN-C was highest in human AAA with the diameter of 45–55 mm, the phase when AAA starts to progress rapidly. TN-C expression in individual aneurysms was highest at the transitional zone between normal and aneurysmal tissue where inflammatory process is most active. In mouse model of AAA induced by periaortic application of CaCl2, TN-C expression increased 4 to 6 weeks after the CaCl2 treatment that coincided with the rapid progression of AAA. Next, we examined if TN-C is involved in the pathogenesis of AAA by creating mouse model with periaortic application of CaCl2 followed by continuous infusion of angiotensin II in wild type (WT) and TN-C knockout (KO) mice. Surprisingly, 5 out of 15 TN-C KO mice developed large suprarenal aneurysms, while none of 14 WT mice did. Histologically, TN-C KO mice showed much more severe inflammation and destruction of elastic lamellae compared to WT. This may be because TN-C-deficient vascular smooth muscle cells express much higher cathepsin S, an elastolytic protease, and inflammatory mediators such as pentraxin 3. These results indicate that TN-C is expressed at the active lesion of AAA and critically involved in the pathogenesis by protecting aorta against tissue destruction. Because serum TN-C reflects the severity of inflammation and is also suitable for bioimaging in various inflammatory diseases, current study suggests that TN-C is an excellent candidate for the therapeutic biomarker and a potential therapeutic target for AAA.

Pharmacological treatment of abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a common degenerative condition with high mortality in older men. Elective surgical or endovascular repair is performed to prevent rupture of large AAAs. In contrast, despite gradual expansion, small AAAs have a low risk of rupture, and there is currently no well-defined treatment strategy for them. Therefore, a pharmacological approach for AAA is expected in the clinical setting. Indeed, several therapeutic effects of pharmacological agents have been reported in experimental models, and some agents have undergone clinical trials. Treatment with statins, angiotensin-converting enzyme-inhibitors, antibiotics, and anti-inflammatory agents appears to inhibit the growth rate of AAA in humans. However, as the sample size and follow-up period were limited in these studies, a large randomized study with long-term follow-up of small AAA should be performed to clarify the effect of these agents. Recently, the regression of AAA using molecular pharmacological approaches was reported in experimental studies. The characteristics of these strategies are the regulation of multiple molecular mediators and the signalling networks associated with AAA formation. On the basis of the results of these investigations, it may be possible to repair the injured aortic wall and obtain the remission of AAA using pharmacological therapy.

Abstract 428: Regression of Abdominal Aortic Aneurysms by Targeting Toll-Like Receptor 2

Abdominal aortic aneurysm (AAA), a chronic inflammatory disorder, results in progressive expansion and rupture of the aorta with high mortality among elderly people. There is increasing evidence that both innate and adaptive immunity tightly regulate the progress of AAA. We recently find that TLR2 plays a critical role in the regulation of wound-repairing process after tissue injury caused by the molecules of pathogen-associated molecular pattern or damage-associated molecular pattern. We wondered if TLR2 had a role in mediating calcium-induced inflammatory responses to participate in the development of AAA in a mice model of CaCl 2 -induced AAA. We found that selectively blocking TLR2 activity using a TLR2-neutralizing antibody not only prevented the development of AAA but also caused regression of well established AAA elicited by incubation of calcium. Furthermore, TLR2 deficient mice failed to develop AAA and had reduced aortic expansion and internal elastic lamina degradation, validating the roles of TLR2 in the development of AAA. The prophylactic and therapeutic effects of blocking TLR2 activity were accompanied by a significant inhibition of vascular fibrosis and inflammation because targeting TLR2 decreased the expressions of α-SMA, matrix metalloproteinase-2/9, and several Th1 and Th2 cytokines such as IFNγ, IL-10, IL-6, TGFβ1 as well as transcription factor Stat3/p-Stat3 in the vascular tissue of AAA. Targeting TLR2 also specifically decreased the expression and extracellular distribution of high-mobility group box 1 and heat shock protein 70, the endogenous TLR2 ligands that sustain chronic inflammation and vascular injury, in the aortic tissue of AAA. In conclusion, our studies demonstrate that TLR2 plays a critical role in the pathogenesis of calcium-induced AAA and highlight unifying mechanisms that blocking TLR2 activity can inhibit specific immune responses induced by calcium and subsequently by HMGB1/HSP70 to modify injury-induced abnormal vascular remodeling. TLR2 is a promising therapeutic target for the prevention and treatment of AAA.

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase

Regression of Abdominal Aortic Aneurysms by Simultaneous Inhibition of Nuclear Factor κB and Ets in a Rabbit Model

Because current therapy to treat abdominal aortic aneurysm (AAA), and particularly to manage small AAA, is limited to elective surgical repair, we explored less invasive molecular therapy by simultaneous inhibition of the transcription factors nuclear factor (NF)kappaB and ets using a decoy strategy. Both NFkappaB and ets were shown to be markedly activated in human AAA. In addition, NFkappaB- and ets-positive cells were increased in the aneurysm wall, and a part of the expression of NFkappaB and ets was detected in migrating macrophages. Thus, we used chimeric decoy oligodeoxynucleotides (ODNs) containing consensus sequences of both NFkappaB and ets binding sites to treat AAA. Inhibitory effects of chimeric decoy ODNs on matrix metalloproteinase-1 and -9 expression were confirmed by ex vivo experiments using a human aorta organ culture. To examine the regressive effect in a rabbit already-formed AAA model, transfection by wrapping a delivery sheet containing chimeric decoy ODNs around the aneurysm was performed 1 week after incubation with elastase. Importantly, treatment with chimeric decoy ODNs significantly decreased the size of AAA. Interestingly, significant preservation of elastic fibers was observed with chimeric decoy ODN treatment, accompanied by a reduction of matrix metalloproteinase-2 and -9 and induction of macrophage apoptosis. Regression of AAA was also associated with an increase in elastin and collagen type I and III synthesis in the aneurysm wall. Minimally invasive molecular therapy targeted to the inhibition of NFkappaB and ets is expected to be useful for AAA through the rebalance of matrix synthesis and degradation.

Turning back the clock: regression of abdominal aortic aneurysms via pharmacotherapy

Abdominal aortic aneurysm (AAA) is a common disease that causes progressive expansion and rupture of the aorta with high mortality. There is a large and unmet need for nonsurgical treatment for AAA. Research has shown that an intricate network of inflammatory cells and interstitial cells contributes to the formation of AAA by producing pro-inflammatory mediators that activate enzymes to degrade the extracellular matrix (ECM) and impair ECM biosynthesis. Pharmacological agents such as statins and angiotensin-converting enzyme inhibitors may promote tissue stabilization in AAA by diminishing pro-inflammatory signaling and normalizing metabolism of the ECM. Our recent experiments in animal models demonstrate that inhibition of c-Jun N terminal kinase (JNK) inhibits multiple pathological processes and causes regression of established AAA. Thus, emerging evidence indicates that pharmacological intervention targeting pro-inflammatory signaling and abnormal ECM metabolism is a promising strategy for treatment of AAA.

Regression of Abdominal Aortic Aneurysm by Inhibition of c‐Jun N‐Terminal Kinase in Mice

Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaCl(2), which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECM biosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl(2)-induced AAA. Furthermore, SP600125 treatment after the establishment of AAA caused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.

Abdominal aortic aneurysm and cerebral aneurysm present different pathological evolutions and responses to pharmacological therapy

Over-degradation of extracellular components by matrix metalloproteinases (MMPs) has been implicated as an important characteristic during the pathological evolution of the abdominal aortic aneurysm (AAA) and cerebral aneurysm (CA), which contribute to progressive dilation of vascular wall. However, mRNA and protein expression of local rennin-angiotensin system (RAS) components are found down-regulated in CA walls, which is contrary to long-holding concept that local RAS will be activated in response to increased hemodynamic stress and contributes to thickening of arterial wall. Similarly, MMPs inhibition by doxycycline effectively ameliorate AAA expansion in basic and clinical researches, but can not reduce the incidence of CA formation in rat. These evidences may suggest that suppression of RAS favors the regression of AAA, but at an increased risk of CA rupture. As the strategies of RAS blockade have became the optimal antihypertensive drugs of choice in clinical arena, the discrepant responses to pharmacologic intervention of AAA and CA should be received considerable attentions, due to their high prevalence in hypertensive population. Here we proposed that AAA and CA, outward remodeling of elastic and muscular arteries respectively, presented with different pathological evolutions and distinct responses to drug intervention, i.e., RAS and MMPs inhibition. It can not be excluded that the potentially deleterious effects of RAS inhibition on CA may be masked by the beneficial action of controlled blood pressure, and the propagation of CA will be exacerbated once suboptimal dose have been prescribed, or under the condition of stress, even drug withdrawal. If the paradoxical outcomes of these two kinds of arterial remodeling were proven true in basic research, clinical use of RAS blockade should be prudent in hypertensive patients, and routine procedures to detect the existence of CA should be considered. Therefore, in depth investigation in their responses to pharmacological approaches will provide us with more insights into the pathogenesis of arterial aneurysm.

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase

Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.

Volume regression of abdominal aortic aneurysms and its relation to successful endoluminal exclusion

Evaluating the success of endoluminal repair of abdominal aortic aneurysms (AAAs) is frequently based on diameter measurements and determining the presence of endoleaks. The use of three-dimensional volumetric data and observation of morphologic changes in the aneurysm and device have been proposed to be more appropriate for postdeployment surveillance. The purpose of this study was to analyze the long-term volumetric and morphologic data of 161 patients who underwent endovascular AAA exclusion and to assess the utility of volume measurements for determining successful AAA repair. Patients with spiral computed tomography scans obtained preoperatively, within the first postoperative month, at 6 months, and annually thereafter, were included in this analysis. Computerized interactive three-dimensional reconstruction of each AAA scan was performed. Total aneurysm sac volume was measured at each time interval (mean preoperative volume 169.0 +/- 78.5 mL), and the significance of volume changes was determined by mixed linear modeling, a form of repeated measures analysis, to account for longitudinal data clustered at the individual level. Sixty-two patients (38%) developed endoleaks at some time during follow-up-15 type I leaks, 45 type II leaks, and 2 type III leaks. The patients with type I and type III leaks were treated with cuffs, and the type II leaks were treated either with observation, side-branch embolization, or required open conversion. Aneurysm sac volume increased slightly at 1-month follow-up (+3.3%), and then decreased steadily to -12.9% at 5 years (P <.0001). This effect remained unchanged after controlling for the three device types used in our study population. Patients who did not exhibit an endoleak (n = 99) showed a significant decrease in aneurysm volume across the entire follow-up duration when compared with those who did exhibit an endoleak (n = 62) (P <.0001). The presence of a 10% or greater decrease in volume at 6 months demonstrated a sensitivity of 64%, a specificity of 95%, a positive predictive value of 95%, a negative predictive value of 62%, and an accuracy of 75% for predicting primary clinical success defined by successful deployment of the device; freedom from aneurysm- or procedure-related death; freedom from endoleak, rupture, migration, or device malfunction; or conversion to open repair. Volumetric analysis may be used to predict successful endoluminal exclusion of AAAs. Volume regression appears to be device-independent and should be expected in most clinically successful cases. The presence of volume increases in the first 6 months is suspicious for an endoleak that is pressurizing the aneurysm sac and heralds the need for closer evaluation and possible intervention. A volume decrease of 10% or greater at 6 months and continuing regression over time is associated with successful endovascular repair.