Bempedoic acid attenuates vascular inflammation and oxidative stress in a preclinical model of abdominal aortic aneurysm.

Salvia miltiorrhiza-Derived Sal-miR-58 Induces Autophagy and Attenuates Inflammation in Vascular Smooth Muscle Cells

Objective: Abdominal aortic aneurysm (AAA) is defined as local weakening and dilatation of the abdominal aorta ≥50% and has high incidence in elderly. Current therapy is limited to surgical repair, only, no pharmacological therapy has shown effectiveness against AAA development and growth. Untreated AAA rupture is highly associated with death, and aged patients are at augmented risk for surgical complications. We therefore sought to identify novel agents that could be employed for medical AAA therapy. Methods: Using whole genome DNA methylation analysis (RRBS-Seq) in a transgenerational model of murine AAA, combined with transcriptional analysis of murine AAA tissue, we identified interferon regulatory factors (IRFs: a group of immune-system-related transcription factors (TF)), as major drivers of AAA risk and pathophysiology. We performed TF enrichment analysis that specifically suggested IRF8 as being crucial for AAA development. Drug Signatures Database (DSigDB) and Connectivity Map (CMap) analysis identified securinine, an alkaloid and traditional Chinese herbal medicine derived from Securinega suffruticosa , as a probable IRF8 inhibitor. Its vascular effects are relatively unknown. Results: We studied the effects of securinine using the porcine pancreatic elastase (PPE) model of AAA. Sonographic imaging data of 28-day securinine-treated mice (15 mg/kg) showed smaller aneurysm diameters and significantly downregulated gene expression of IRF8 and IFN-γ compared to control PPE groups. Conclusion: These data suggest that securinine may have therapeutic benefits on AAA development, potentially through regulation of IRF8.

Abdominal aortic aneurysms (AAAs) represent a complex degenerative disorder involving chronic aortic wall inflammation and destructive remodeling of structural connective tissue. Studies using human AAA tissues have helped identify a variety of molecular mediators and matrix-degrading proteinases, which contribute to aneurysm disease, thereby providing a sound foundation for understanding AAAs; however, these human tissue specimens represent only the "end stage" of a long and progressive disease process. Further progress in understanding the pathophysiology of AAAs is therefore dependent in part on the development and application of effective animal models that recapitulate key aspects of the disease. Based on original studies in rats, transient perfusion of the abdominal aorta with porcine pancreatic elastase has provided a reproducible and robust model of AAAs. More recent applications of this model to mice have also opened new avenues for investigation. In this review, we summarize investigations using the elastase-induced mouse model of AAAs including results in animals with targeted deletion of specific genes and more general differences in mice on different genetic backgrounds. These studies have helped us identify genes that are essential to the development of AAAs (such as MMP9, IL6, and AT1R) and to reveal other genes that may be dispensable in aneurysm formation. Investigations on mice from different genetic backgrounds are also beginning to offer a novel approach to evaluate the genetic basis for susceptibility to aneurysm development.

Anatomical repair of a congenital aneurysm of the distal abdominal aorta in a newborn

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Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture. Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.

Background and Objective: Iron accumulation and increased oxidative stress contribute to the pathophysiology of abdominal aortic aneurysm (AAA). Intracellular iron transport is regulated by transferrin receptor 1 (TfR1), and up-regulation of aortic TfR1 expression has been reported in human and mouse AAA tissues. The aim of this study is to examine whether TfR1 deletion attenuates AAA formation. Methods: Since TfR1 homozygous deletion causes embryonic lethality due to hematopoietic defect, heterozygous TfR1 deleted mice were used and were crossbred with apolipoprotein E deleted (ApoE -/- ) mice (DKO). To induce AAA, subcutaneous infusion of angiotensin II (AngII, 1,000 ng/kg/min) was performed for 4 weeks in heterozygous TfR1 deleted mice. Wild type littermates and saline infusion were used as controls. Results: Abdominal aortic rupture rate was not significantly different between ApoE -/- and DKO mice during AngII infusion (21% vs 9%, p =0.29). In the survivors, aortic dimension was measured in ex vivo, and it was decreased in DKO mice compared to AngII-infused ApoE -/- mice (2.0 ± 0.2 vs 1.6 ± 0.1 mm, p < 0.05). Berlin blue staining revealed that iron was accumulated in the adventitia of aneurysmal lesions in AngII-infused ApoE -/- mice, whereas this accumulation was suppressed by TfR1 deletion. Immunostaining for 4hydoxy-2-nonenal (4-HNE), a maker of oxidative stress, was performed to examine aortic oxidative stress. The extent of 4-HNE positive area was significantly elevated in the aneurysmal lesions of AngII-infused ApoE -/- mice, whereas these were attenuated in DKO mice. In addition, aortic inflammation was examined by immunostaining for CD45 and CD68. Consistent with the results of Berlin blue and 4-NHE staining, CD45 and CD68 positive areas were decreased in the aorta of AngII-infused DKO mice compared to that of ApoE -/- mice. Conclusions: Heterozygous deletion of TfR1 attenuated AngII-induced AAA formation. TfR1 is a novel therapeutic target for the prevention of AAA.

The impact of leukotriene production by the 5-lipoxygenase (5-LO) pathway in the pathophysiology of abdominal aortic aneurysms (AAAs) has been debated. Moreover, a clear mechanism through which 5-LO influences AAA remains unclear. Aneurysm formation was attenuated in 5-LO(-/-) mice, and in lethally irradiated wild-type mice reconstituted with 5-LO(-/-) bone marrow in an elastase perfusion model. Pharmacological inhibition of 5-LO-attenuated aneurysm formation in both aortic elastase perfused wild-type and angiotensin II-treated LDLr(-/-) (low-density lipoprotein receptor) mice, with resultant preservation of elastin and fewer 5-LO and MMP9 (matrix metalloproteinase)-producing cells. Separately, analysis of wild-type mice 7 days after elastase perfusion showed that 5-LO inhibition was associated with reduced polymorphonuclear leukocyte infiltration to the aortic wall. Importantly, 5-LO inhibition initiated 3 days after elastase perfusion in wild-type mice arrested progression of small AAA. Human AAA and control aorta corroborated these elastin and 5-LO expression patterns. Inhibition of 5-LO by pharmacological or genetic approaches attenuates aneurysm formation and prevents fragmentation of the medial layer in 2 unique AAA models. Administration of 5-LO inhibitor in small AAA slows progression of AAA. Targeted interruption of the 5-LO pathway is a potential treatment strategy in AAA.

Aortic diseases are common in many populations and are receiving increasing research focus. There are a broad spectrum of aortic diseases that occur in specific regions and appear to have different causes. For example, abdominal aortic aneurysms (AAAs) are most common in aged men.1 In contrast, many forms of thoracic aortic aneurysms (TAAs) occur early in life with a strong genetic basis and no sex discrimination.2 Both aortic aneurysms are amenable to surgical repair. Although surgical approaches have become increasingly sophisticated and less invasive,3 there remains an urgent need to determine factors that predispose to susceptibility and to divert treatment from surgical to medical approaches.4,5 This switch to medical treatment will require an increased knowledge of the mechanisms for several facets of aneurysms that cover the span of initiation, progression, and rupture. In this regard, many recent publications in ATVB have provided further insight into established pathways contributing to aneurysm development such as proteolysis, inflammation, and attenuation of the medial smooth muscle cell population, and a few publications have raised the possibility of new pathways such as adipokines and mineralocorticoid signaling. This article highlights these recent publications within a brief context of the literature. Cigarette smoking remains the major risk factor for development and progression of AAAs.6,7 Several experimental studies have demonstrated that smoke exposure augments AAA induced in mice by either subcutaneous angiotensin II (AngII) infusion or intra-aortic elastase perfusion.8,9 However, it is unclear whether cessation of smoking impacts the development of AAAs. The study of Jin et al10 demonstrated that cessation of cigarette smoking exposure did not immediately decrease the augmentation of AAAs. This sustained effect was attributable to regulation of leukocytic metabolism. Also of note is that cigarette smoking–induced augmentation of AAAs was unaffected …

A Novel Murine Model of Early Abdominal Aortic Aneurysm Reflects Immunopathology in Human Abdominal Aortic Aneurysms

Prostanoids are a large family of lipid mediators derived from the arachidonic acid metabolites of the cyclooxygenase (COX) enzymes. Therapeutically, COX is the target of the nonsteroid antiinflammatory drugs (NSAIDs), a chemically diverse group that includes ibuprofen, naproxen, and diclofenac, among dozens of others. Inhibition of prostanoid production by traditional NSAIDs accounts for all their major therapeutic effects, such as the dampening down of inflammation and the reduction of fever, and their potentially severe adverse side effects, most commonly within the gastrointestinal tract.1,2 See page 1137 Since the early 1990’s it has been clear there are two distinct enzymes responsible for the production of prostanoids: a constitutive COX-1 found in all tissues and an inflammation-associated enzyme COX-2.1,2 COX-2 is constitutively expressed in only a few sites, such as parts of the kidney and central nervous system, but is highly upregulated and active at sites of inflammation. These findings led to the hypothesis that selective COX-2 inhibitors could be antiinflammatory without the major side effects associated with traditional NSAIDs. Against this background several COX-2–selective inhibitors have been produced and brought to market, the first two being celecoxib (Celebrex) and rofecoxib (Vioxx). Preclinical studies of these COX-2–selective inhibitors were extremely promising. In animal models, for example, they were demonstrated to be as efficacious as traditional NSAIDs but to be lacking their toxic actions on the gastrointestinal tract. Clinical trials have, however, been marred by controversy. The CLASS trial for celecoxib, a 12-month osteoarthritis study of celecoxib, demonstrated celecoxib to have improved safety relative to ibuprofen but not …

Inflammatory Gene Expression of Human Perivascular Adipose Tissue in Abdominal Aortic Aneurysms

Intra-aortic infusion of nicotine can induce a novel mouse model of abdominal aortic aneurysm.

Rolipram impacts on redox homeostasis and cellular signaling in an experimental model of abdominal aortic aneurysm

The main pathophysiology of abdominal aortic aneurysm (AAA) considerably overlaps with that of atherosclerosis. We reported that incretins [glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP)] or a dipeptidyl peptidase-4 inhibitor (DPP-4I) suppressed atherosclerosis in apolipoprotein E-null (Apoe－/－) mice. Here we investigated the effects of incretin-related agents on AAA in a mouse model. Apoe－/－ mice maintained on an atherogenic diet were subcutaneously infused with saline, Ang II (2000 ng/kg/min), Ang II, and native GLP-1 (2.16 nmol/kg/day) or Ang II and native GIP (25 nmol/kg/day) for 4 weeks. DPP-4I (MK0626, 6 mg/kg/day) was provided in the diet to the Ang II-infused mice with or without incretin receptor antagonists [(Pro3) GIP and exendin (9-39)]. AAA occurred in 70% of the animals receiving Ang II. DPP-4I reduced this rate to 40% and significantly suppressed AAA dilatation, fibrosis, and thrombosis. In contrast, incretins failed to attenuate AAA. Incretin receptor blockers did not reverse the suppressive effects of DPP-4I on AAA. In the aorta, DPP-4I significantly reduced the expression of Interleukin-1β and increased that of tissue inhibitor of metalloproteinase (TIMP)-2. In addition, DPP-4I increased the ratio of TIMP-2 to matrix metalloproteinases-9. DPP-4I, MK0626, but not native incretins has protective effects against AAA in Ang II-infused Apoe－/－ mice via suppression of inflammation, proteolysis, and fibrosis in the aortic wall.