Abdominal Aortic Aneurysm Initiation Research Articles

GP VI-Mediated Platelet Activation and Procoagulant Activity Aggravate Inflammation and Aortic Wall Remodeling in Abdominal Aortic Aneurysm.

Platelets play an important role in cardiovascular and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerosis-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall, accompanied by chronic inflammation. Platelet activation and procoagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and humans. The present study investigated the impact of the major platelet collagen receptor GP (platelet glycoprotein) VI in pathophysiological processes underlying AAA initiation and progression. For experimental AAA induction in mice, PPE (porcine pancreatic elastase) and the external PPE model were used. Genetic deletion of GP VI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GP VI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Furthermore, remodeling of the aortic wall was improved in the absence of GP VI, as indicated by reduced MMP (matrix metalloproteinase)-2/9 and OPN (osteopontin) plasma levels and an enhanced α-SMA (α-smooth muscle actin) content within the aortic wall, accompanied by reduced cell apoptosis. Consequently, an elevation in intima/media thickness and elastin content was observed in GP VI-deficient PPE mice, resulting in a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In patients with AAA, enhanced plasma levels of soluble GP VI and fibrin, as well as fibrin accumulation within the intraluminal thrombus might serve as new biomarkers to detect AAA early. Moreover, we hypothesize that GP VI might play a role in procoagulant activity and thrombus stabilization via binding to fibrin. In conclusion, our results emphasize the potential need for a GP VI-targeted antiplatelet therapy to reduce AAA initiation and progression, as well as to protect patients with AAA from aortic rupture.

Comprehensive analysis identified a reduction in ATP1A2 mediated by ARID3A in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is characterized by abdominal aorta dilatation and progressive structural impairment and is usually an asymptomatic and potentially lethal disease with a risk of rupture. To investigate the underlying mechanisms of AAA initiation and progression, seven AAA datasets related to human and mice were downloaded from the GEO database and reanalysed in the present study. After comprehensive bioinformatics analysis, we identified the enriched pathways associated with inflammation responses, vascular smooth muscle cell (VSMC) phenotype switching and cytokine secretion in AAA. Most importantly, we identified ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) as a key gene that was significantly decreased in AAA samples of both human and mice; meanwhile, its reduction mainly occurred in VSMCs of the aorta; this finding was validated by immunostaining and Western blot in human and mouse AAA samples. Furthermore, we explored the potential upstream transcription factors (TFs) that regulate ATP1A2 expression. We found that the TF AT‐rich interaction domain 3A (ARID3A) bound the promoter of ATP1A2 to suppress its expression. Our present study identified the ARID3A‐ATP1A2 axis as a novel pathway in the pathological processes of AAA, further elucidating the molecular mechanism of AAA and providing potential therapeutic targets for AAA.

Abdominal Aortic Aneurysm Formation with a Focus on Vascular Smooth Muscle Cells.

Abdominal aortic aneurysm (AAA) is a lethal degenerative vascular disease that affects, mostly, the elder population, with a high mortality rate (>80%) upon rupture. It features a dilation of the aortic diameter to larger than 30 mm or more than 50%. Diverse pathological processes are involved in the development of AAA, including aortic wall inflammation, elastin breakdown, oxidative stress, smooth muscle cell (SMC) phenotypic switching and dysfunction, and extracellular matrix degradation. With open surgery being the only therapeutic option up to date, the lack of pharmaceutical treatment approach calls for identifying novel and effective targets and further understanding the pathological process of AAA. Both lifestyle and genetic predisposition have an important role in increasing the risk of AAA. Several cell types are closely related to the pathogenesis of AAA. Among them, vascular SMCs (VSMCs) are gaining much attention as a critical contributor for AAA initiation and/or progression. In this review, we summarize what is known about AAA, including the risk factors, the pathophysiology, and the established animal models of AAA. In particular, we focus on the VSMC phenotypic switching and dysfunction in AAA formation. Further understanding the regulation of VSMC phenotypic changes may provide novel therapeutic targets for the treatment or prevention of AAA.

Twenty Years of Studying AngII (Angiotensin II)-Induced Abdominal Aortic Pathologies in Mice: Continuing Questions and Challenges to Provide Insight Into the Human Disease.

AngII (angiotensin II) infusion in mice has been used to provide mechanistic insight into human abdominal aortic aneurysms for over 2 decades. This is a technically facile animal model that recapitulates multiple facets of the human disease. Although numerous publications have reported abdominal aortic aneurysms with AngII infusion in mice, there remain many fundamental unanswered questions such as uniformity of describing the pathological characteristics and which cell type is stimulated by AngII to promote abdominal aortic aneurysms. Extrapolation of the findings to provide insight into the human disease has been hindered by the preponderance of studies designed to determine the effects on initiation of abdominal aortic aneurysms, rather than a more clinically relevant scenario of determining efficacy on the established disease. The purpose of this review is to enhance understanding of AngII-induced abdominal aortic pathologies in mice, thereby providing greater insight into the human disease.

Recombinant Interleukin-19 Suppresses the Formation and Progression of Experimental Abdominal Aortic Aneurysms.

BackgroundInterleukin‐19 is an immunosuppressive cytokine produced by immune and nonimmune cells, but its role in abdominal aortic aneurysm (AAA) pathogenesis is not known. This study aimed to investigate interleukin‐19 expression in, and influences on, the formation and progression of experimental AAAs.Methods and ResultsHuman specimens were obtained at aneurysm repair surgery or from transplant donors. Experimental AAAs were created in 10‐ to 12‐week‐old male mice via intra‐aortic elastase infusion. Influence and potential mechanisms of interleukin‐19 treatment on AAAs were assessed via ultrasonography, histopathology, flow cytometry, and gene expression profiling. Immunohistochemistry revealed augmented interleukin‐19 expression in both human and experimental AAAs. In mice, interleukin‐19 treatment before AAA initiation via elastase infusion suppressed aneurysm formation and progression, with attenuation of medial elastin degradation, smooth‐muscle depletion, leukocyte infiltration, neoangiogenesis, and matrix metalloproteinase 2 and 9 expression. Initiation of interleukin‐19 treatment after AAA creation limited further aneurysmal degeneration. In additional experiments, interleukin‐19 treatment inhibited murine macrophage recruitment following intraperitoneal thioglycolate injection. In classically or alternatively activated macrophages in vitro, interleukin‐19 downregulated mRNA expression of inducible nitric oxide synthase, chemokine C‐C motif ligand 2, and metalloproteinases 2 and 9 without apparent effect on cytokine‐expressing helper or cytotoxic T‐cell differentiation, nor regulatory T cellularity, in the aneurysmal aorta or spleen of interleukin‐19–treated mice. Interleukin‐19 also suppressed AAAs created via angiotensin II infusion in hyperlipidemic mice.ConclusionsBased on human evidence and experimental modeling observations, interleukin‐19 may influence the development and progression of AAAs.

Identification of key genes and pathways involved in abdominal aortic aneurysm initiation and progression.

The study aimed to assess the gene expression profile of biopsies obtained from the neck of human abdominal aortic aneurysm (AAA) and the main site of AAA dilatation and to investigate the molecular mechanism underlying the development of AAA. The microarray profile of GSE47472 and GSE57691 were obtained from the Gene Expression Omnibus (GEO) database. The GSE47472 was a microarray dataset of tissues from the aortic neck of AAA patients versus normal controls. The GSE57691 was a microarray dataset including the tissues from main site of AAA dilatation versus normal controls. Differentially expressed genes (DEGs) were chosen using the R package and annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG). The hub genes were identified in the protein-protein interaction (PPI) network. 342 upregulated DEGs and 949 downregulated DEGs were obtained from GSE47472. The upregulated DEGs were mainly enriched in biological regulation (ontology: BP), the membrane (ontology: CC), and protein binding (ontology: MF), and the downregulated genes were mainly enriched in biological regulation (ontology: BP), the membrane (ontology: CC), and protein blinding (ontology: MF). In the KEGG enrichment analysis, the DEGs mainly involved glycosaminoglycan degradation, vasopressin-regulated water reabsorption, and pyruvate metabolism. The hub genes in GSE47472 mainly include VAMP8, PTPRC, DYNLL1, RPL38, RPS4X, HNRNPA1, PRMT1, TGOLN2, PA2G4, and CUL2. From GSE57691, 248 upregulated DEGs and 1120 downregulated DEGs were selected. The upregulated DEGs of GSE57691 were mainly enriched in biological regulation (ontology: BP), the membrane (ontology: CC), and protein binding (ontology: MF), and the downregulated genes were mainly enriched in metabolic process (ontology: BP), the membrane (ontology: CC), and protein blinding (ontology: MF). In the KEGG enrichment analysis, the DEGs mainly involved the mitochondrial respiratory, respiratory chain complex, and respiratory chain. RPS15A, RPS5, RPL23, RPL27A, RPS24, RPL35A, RPS4X, RPL7, RPS25, and RPL21 were identified as the hub genes. At the early stage of AAA, the current study indicated the importance of glycosaminoglycan degradation and anaerobic metabolism. We also identified several hub genes closely related to AAA (VAMP8, PTPRC, DYNLL1, etc.). At the progression of the AAA, the dysfunctional mitochondria played a critical role in AAA formation and the RPS15A, RPS5, RPL23, etc., were identified as the hub genes.

FRZB as a key molecule in abdominal aortic aneurysm progression affecting vascular integrity.

Abdominal aortic aneurysm (AAA), when ruptured, results in high mortality. The identification of molecular pathways involved in AAA progression is required to improve AAA prognosis. The aim of the present study was to assess the key genes for the progression of AAA and their functional role. Genomic and clinical data of three independent cohorts were downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (GSE57691, GSE7084, and GSE98278). To develop AAA diagnosis and progression-related differentially expressed genes (DEGs), we used a significance analysis of microarray (SAM). Spearman correlation test and gene set analysis were performed to identify potential enriched pathways for DEGs. Only the Frizzled-related protein (FRZB) gene and chromosome 1 open reading frame 24 (C1orf24) exhibited significant down-regulation in all analyses. With FRZB, the pathways were associated with RHO GTPase and elastin fiber formation. With C1orf24, the pathways were elastic fiber formation, extracellular matrix organization, and cell–cell communication. Since only FRZB was evolutionally conserved in the vertebrates, function of FRZB was validated using zebrafish embryos. Knockdown of frzb remarkably reduced vascular integrity in zebrafish embryos. We believe that FRZB is a key gene involved in AAA initiation and progression affecting vascular integrity.

Chronic Intermittent Hypoxia Regulates CaMKII-Dependent MAPK Signaling to Promote the Initiation of Abdominal Aortic Aneurysm.

Obstructive sleep apnea (OSA) is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, the effects of OSA on AAA initiation in a murine model of sleep apnea have not been completely studied. In this paper, Apoe−/− C57BL/6 mice infused with angiotensin II (Ang II) were placed in chronic intermittent hypoxia (CIH) condition for inducing OSA-related AAA. CIH significantly promoted the incidence of AAA and inhibited the survival of mice. By performing ultrasonography and elastic Van Gieson staining, CIH was found to be effective in promoting aortic dilation and elastin degradation. Immunohistochemical and zymography results show that CIH upregulated the expression and activity of MMP2 and MMP9 and upregulated MCP1 expression while downregulating α-SMA expression. Also, CIH exposure promoted ROS generation, apoptosis, and mitochondria damage in vascular smooth muscle cells (VSMCs), which were measured by ROS assay, TUNEL staining, and transmission electron microscopy. The result of RNA sequencing of mouse aortas displayed that 232 mRNAs were differently expressed between Ang II and Ang II+CIH groups, and CaMKII-dependent p38/Jnk was confirmed as one downstream signaling of CIH. CaMKII-IN-1, an inhibitor of CaMKII, eliminated the effects of CIH on the loss of primary VSMCs. To conclude, a mouse model of OSA-related AAA, which contains the phenotypes of both AAA and OSA, was established in this study. We suggested CIH as a risk factor of AAA initiation through CaMKII-dependent MAPK signaling.

Human Umbilical Cord Mesenchymal Stem Cells Attenuate Abdominal Aortic Aneurysm Progression in Sprague-Dawley Rats: Implication of Vascular Smooth Muscle Cell Phenotypic Modulation.

Abdominal aortic aneurysm (AAA) is life-threatening, for which efficient nonsurgical treatment strategy has not been available so far. Several previous studies investigating the therapeutic effect of mesenchymal stem cells (MSCs) in AAA indicated that MSCs could inhibit aneurysmal inflammatory responses and extracellular matrix destruction, and suppress aneurysm occurrence and expansion. Vascular smooth muscle cell (VSMC) phenotypic plasticity is reported to be predisposed in AAA initiation and progression. However, little is known about the effect of MSCs on VSMC phenotypic modulation in AAA. In this study, we investigate the therapeutic efficacy of umbilical cord mesenchymal stem cells (UC-MSCs) in elastase-induced AAA model and evaluate the effect of UC-MSC on VSMC phenotypic regulation. We demonstrate that the intravenous injection of UC-MSC attenuates elastase-induced aneurysmal expansion, reduces elastin degradation and fragmentation, inhibits MMPs and TNF-α expression, and preserves and/or restores VSMC contractile phenotype in AAA. Taken together, these results highlight the therapeutic and VSMC phenotypic modulation effects of UC-MSC in AAA progression, which further indicates the potential of applying UC-MSC as an alternative treatment candidate for AAA.

Abstract 058: Efficacy and Mechanisms of Metformin Therapy in Established Experimental Abdominal Aortic Aneurysms

Objective: Diabetes reduces the risk for abdominal aortic aneurysm (AAA) disease. In prior work in rodent models, pre-treatment with metformin was protective against experimental AAA initiation and progression. This study examined the influence of metformin therapy on progression of existing experimental AAAs. Methods: AAAs were created in 10-12 week old male C57BL/6J mice via transient intra-aortic infusion of porcine pancreatic elastase (PPE). Mice were treated with metformin (250 mg/kg via oral gavage), metformin plus AMPK inhibitor Compound C (the later via 10 mg/kg intraperitoneal injection) or vehicle alone for 10 days starting on day 4 following AAA creation. Outcomes were assessed by serial transabdominal ultrasonographic assessment of aortic diameter during treatment, as well as histological examination at sacrifice. Results: The principal findings are summarized in the Figure. Vehicle-treated mice experienced progressive, time-dependent aortic enlargement from day 3 to 14 following PPE infusion. Metformin treatment substantially attenuated further enlargement of existing AAAs. Treatment with Compound C partially rescued the AAA phenotype in metformin-treated mice. Histologically, characteristic aneurysmal pathologic changes, including medial elastin degradation, smooth muscle cell (SMC) depletion, mural leukocyte accumulation and neoangiogenesis (assessed by CD31 staining), present in PPE-infused, vehicle-treated mice, were substantially attenuated with metformin treatment. Co-treatment with Compound C abrogated the effects of metformin on media elastin degradation, SMC depletion and mural macrophage infiltration, with less influence on mural angiogenesis. Conclusion: Metformin therapy suppresses further expansion of existing experimental AAAs. This effect is abrogated by co-treatment with Compound C. These findings further justify performance of a clinical trial of metformin for medical management of AAA disease.

Abstract 713: Angiotensin 1-7 Suppresses Experimental Abdominal Aortic Aneurysms

Objectives: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, the pathogenesis of which remains incompletely defined. We and others have demonstrated the critical role of angiotensin (Ang) II and its receptor AT1 in experimental AAAs. Although Ang 1-7 and its receptor Mas counteract many AT1 functions, the role of the Ang 1-7/Mas pathway has not been studied in AAAs. This study evaluated the influences of Ang 1-7 and Mas on experimental AAAs. Methods: AAAs were created in male C57BL/6J mice via porcine pancreatic elastase (PPE) infusion. Mice were treated with Ang 1-7 (0.5 mg/kg/day via s.c) or vehicle starting immediately prior to, or 4 days following, PPE infusion. Additional mice were co-treated with Ang 1-7 and the Mas receptor antagonist A779 (0.5 mg/kg/day) beginning immediately prior to PPE infusion. Influences on AAAs were evaluated by serial ultrasound imaging and histology. Results: Figure summarizes major results. In ultrasound imaging, at 14 days Ang 1-7 treatment initiated immediately following aneurysm creation substantially suppressed aortic enlargement as compared to vehicle treatment. Histologically, Ang 1-7 treatment was associated with attenuation of aortic medial elastin and smooth muscle cell depletion, mural macrophage, CD4 + , CD8 + T and B cell density and neoangiogenesis. Co-treatment with Ang 1-7 receptor Mas antagonist A779 “rescued” the aneurysm phenotype. Additionally, Ang 1-7 treatment initiated even 4 days following AAA creation was still effective in limiting further aneurysmal enlargement and pathologic evolution. Conclusions: Ang 1-7 treatment, initiated either at, or up to 4 days following, AAA initiation limits further progression of experimental AAAs. This inhibitory effect seems likely related to activation of the Mas receptor. These results suggest that either Ang 1-7 or alternative Mas receptor agonists may have clinical utility in suppressing progression of early AAA disease.

High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice.

Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman's rho -0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19-0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1-/-ApoE-/-, n=20) and control mice (ApoE-/-, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1-/- ApoE-/- mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1-/-ApoE-/- mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1-/-ApoE-/- mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1-/-ApoE-/- mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.

Inhibition of BET bromodomain attenuates angiotensin II induced abdominal aortic aneurysm in ApoE−/− mice

BackgroundExcessive degradation of extracellular matrix by matrix metalloproteinases (MMP) is the major pathological feature of abdominal aortic aneurysm (AAA). Suppression of extracellular matrix degradation attenuates AAA initiation and progression in preclinical models. In the present study, we wanted to test the effect of JQ1, a small chemical molecule that selectively targets bromodomain and extra-terminal domain (BET), on AngII induced AAA formation in ApoE−/− mice. Methods and resultsTo study the role of BET bromodomain in AAA pathogenesis, male ApoE−/− mice were infused with angiotensin II (AngII, 1000ng/kg/min) for 21days and cotreated with JQ1 (50mg/kg daily) or vehicle control (DMSO). In the in vitro study, we determined the mRNA expression of MMP genes by qPCR and their activity both by the kit and gelatin zymography assay. BET bromodomain inhibition resulted in decreased abdominal aortic diameter (P<0.05) measured by in vivo vascular ultrasound and ex vivo pathologic assessment of aortas. In pursuit of mechanisms for this effect on AAA, we observed that JQ1 treatment led to a downregulation of metalloproteinase gene expression and enzymatic activity both in vitro and in vivo. ConclusionsBET bromodomain inhibition improved AAA pathological sequelae, and this effect might be achieved though suppression of MMP genes expression and their activity.

Correspondence on: "Therapeutic Prospect of Adipose-Derived Stromal Cells for Treatment of Abdominal Aortic Aneurysm".

We are quite interested in the important review by M. Parvizi and M.C. Harmsen, published on February 23, 2015, in Stem Cells and Development [1]. The authors pointed out that studies failed to explain the initial trigger and initiation of abdominal aortic aneurysm (AAA) in animal studies. The typical chicken or egg question also arouses our enormous interest. To answer this question, we successfully induce a novel model of enlarging AAA in rabbits by a combination of elastase incubation and aortic coarctation [2]. Our model successfully overcomes the self-healing phenomenon in elastase-induced AAA and indicated that hemodynamic change is vital to the initiation and progression of AAA by a certain mechanism. The onset of AAA diseases involves the activation of the endothelial cells [1]. A decreased endothelial recovery was shown in our experiment; perhaps, endothelial cells are vital to the initiation of AAA under the influence of hemodynamics. The authors pointed out that smooth muscle cells (SMCs), the main workhorse of an artery, not only serve a contractile role but in addition produce, deposit, and continuously remodel the vascular extracellular matrix. We quite appreciate this point and hypothesize that SMCs account for self-healing of AAA model. In our previous studies, matrix metalloproteinase (MMP)2 kept moderate expression during a 5-month follow-up [3], and a similar expression was shown in enlarging AAA; however, the increased expressions are not proportionate to the enlargement of AAA. Aneurysm develops after infusion of elastase due to an inflammatory cascade that ultimately leads to matrix degradation by MMPs. This classical theory indicates that MMPs play an evil role in AAA formation, and it seems scientific to treat AAA by inhibiting MMPs. However, we hypothesize that MMPs, especially MMP2, play a positive role in the complex remodeling of aneurysmal wall, which then cause a self-healing of AAA. Shen et al. found that MMP2 plays two opposing roles in aortic wall remodeling [4]. Interestingly, so many treatments, including the MMP inhibitor, achieved perfect results in animal studies; however, few are of benefit to human AAA diseases. It seems more reasonable to treat AAA by enhancing the repair progress of aneurysmal wall, such as promoting SMCs adjacent to aneurysm migration and proliferation to some rational degree. Besides, the ‘‘response to injury’’ hypothesis suggests that SMCs migrate and subsequently proliferate after injury, and the contractile SMCs be modulated back into the synthetic phenotype and participate in tissue repair [5]. It seems feasible and beneficial to promote and restore the phenotype of the affected medial SMCs.

E-016 A Comparative Review of the Hemodynamics and Pathogenesis of Cerebral and Abdominal Aortic Aneurysms: Lessons to Learn From Each Other

Introduction/purposeCerebral aneurysms (CAs) and abdominal aortic aneurysms (AAAs) are both degenerative vascular pathologies that manifest as an abnormal dilation of the arterial wall. They arise with different morphologies in different...

Abstract 18459: MicroRNA-712 Induced by Angiotensin II Plays a Key Role in Development of Abdominal Aortic Aneurysm in Mouse

Abdominal aortic aneurysm (AAA) is a complex vascular disease and a major cause of mortality. AAA is characterized by a weakening of the vessel wall, followed by progressive expansion of the diseased aortic segment. Although the molecular mechanisms underlying AAA initiation and development are poorly understood, microRNAs (miRNAs) are thought to play a role in these processes. Here we identify microRNA-712 (miR-712) through a microRNA array study as a novel miRNA upregulated in abdominal aortic endothelium in mice infused with angiotensin II (AngII, 1 ug/kg/min for 12 to 36 hours). Through in silico analysis and using gain-of-function [pre-miR-712] and loss-of-function [locked nucleic acid (LNA)-based anti-miR-712] studies, we determined that miR-712 directly regulates the expression of tissue inhibitor of metalloproteinase 3 (TIMP3). Additionally, we confirmed the target-binding activity of miR-712 on the 3’UTR of TIMP3 by dual-luciferase reporter assay. Furthermore, inhibition of miR-712 decreased matrix metalloproteinase (MMP) activity in an AngII-infused abdominal aorta wall. Finally, we showed that inhibition of AngII-induced miR-712 by subcutaneous injection of anti-miR-712 reduced AAA incidence from 80% (8/10) to 20% (2/10) and maximal aortic diameter from 2.1±0.6mm to 1.2±0.4 mm compared to mismatched control in ApoE -/- mice via MMP-mediated mechanisms. Our findings show that miR-712 regulates MMPs activity through the endogenous regulator TIMP3, which leads us to conclude that AngII-induced miRNAs such as miR-712 play important roles in the pathogenesis of AAA. These results suggest that manipulation of miR-712, and its target gene TIMP3 may hold promise as a therapeutic strategy to prevent the development of AAA.

Micromanaging Abdominal Aortic Aneurysms

The contribution of abdominal aortic aneurysm (AAA) disease to human morbidity and mortality has increased in the aging, industrialized world. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of the diseased aorta. This work aims to develop novel diagnostic and therapeutic strategies to limit AAA expansion and, ultimately, rupture. Contributions from multiple research groups have uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining aortic vascular homeostasis. Recently, novel small noncoding RNAs, called microRNAs, have been identified as important transcriptional and post-transcriptional inhibitors of gene expression. MicroRNAs are thought to “fine tune” the translational output of their target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. With the discovery that microRNAs act as powerful regulators in the context of a wide variety of diseases, it is only logical that microRNAs be thoroughly explored as potential therapeutic entities. This current review summarizes interesting findings regarding the intriguing roles and benefits of microRNA expression modulation during AAA initiation and propagation. These studies utilize disease-relevant murine models, as well as human tissue from patients undergoing surgical aortic aneurysm repair. Furthermore, we critically examine future therapeutic strategies with regard to their clinical and translational feasibility.