Inhibition of Receptor-Interacting Protein Kinase 1 with Necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model.
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ABSTRACT:
SUBMITTER: Wang Q
PROVIDER: S-EPMC5301478 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Inhibition of Receptor-Interacting Protein Kinase 1 with Necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model.
Wang Qiwei Q Zhou Ting T Liu Zhenjie Z Ren Jun J Phan Noel N Gupta Kartik K Stewart Danielle M DM Morgan Stephanie S Assa Carmel C Kent K Craig KC Liu Bo B
Scientific reports 20170210
Abdominal aortic aneurysm (AAA) is a common aortic disease with a progressive nature. There is no approved pharmacological treatment to effectively slow aneurysm growth or prevent rupture. Necroptosis is a form of programmed necrosis that is regulated by receptor-interacting protein kinases (RIPs). We have recently demonstrated that the lack of RIP3 in mice prevented aneurysm formation. The goal of the current study is to test whether perturbing necroptosis affects progression of existing aneury ...[more]
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Project description:Abstract: The pathogenesis of AAA involves vascular inflammation and oxidative stress. Astragali Radix contains cycloastragenol (CAG) known to have anti-inflammatory and anti-oxidative properties. We hypothesized that CAG supplement impairs AAA progression. AAA was induced in male rats by intraluminal elastase infusion in the infrarenal aorta and treated daily with CAG (125 mg/kg/day). Aortic expansion was followed weekly by ultrasound, with euthanization at day 28. Changes in AAA wall composition were analyzed at mRNA levels, histology, zymography and explorative proteomic analyses. At day 28, mean AAA diameter was 37% lower in CAG group (p<0.0001). In aneurysm cross sections, elastin content was insignificantly higher in CAG group (10.5% ± 5.9% vs 19.9% ± 16.8%, p=0.20) with more preserved elastin lamellae structures (p=0.0003) and with no microcalcifications. Aneurysmal matrix metalloprotease-2 activity was reduced by CAG treatment (p=0.022), and mRNA levels of inflammatory- and antioxidative markers showed no difference between groups. Explorative proteomic analysis showed no difference in protein levels when adjustment for multiple testing. Amongst unadjusted affected proteins were fibulin-5 (p=0.02), aquaporin-1 (p=0.02) and prostacyclin synthase (p=0.006). CAG impairs experimental AAA progression by reduction of elastin degradation through decreased MMP-2 activity, thus CAG could be considered tested in AAA patients.
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Project description:The pathogenesis of abdominal aortic aneurysm involves vascular inflammation and elastin degradation. Astragalusradix contains cycloastragenol, which is known to be anti-inflammatory and to protect against elastin degradation. We hypothesized that cycloastragenol supplementation inhibits abdominal aortic aneurysm progression. Abdominal aortic aneurysm was induced in male rats by intraluminal elastase infusion in the infrarenal aorta and treated daily with cycloastragenol (125 mg/kg/day). Aortic expansion was followed weekly by ultrasound for 28 days. Changes in aneurysmal wall composition were analyzed by mRNA levels, histology, zymography and explorative proteomic analyses. At day 28, mean aneurysm diameter was 37% lower in the cycloastragenol group (p < 0.0001). In aneurysm cross sections, elastin content was insignificantly higher in the cycloastragenol group (10.5% ± 5.9% vs. 19.9% ± 16.8%, p = 0.20), with more preserved elastin lamellae structures (p = 0.0003) and without microcalcifications. Aneurysmal matrix metalloprotease-2 activity was reduced by the treatment (p = 0.022). Messenger RNA levels of inflammatory- and anti-oxidative markers did not differ between groups. Explorative proteomic analysis showed no difference in protein levels when adjusting for multiple testing. Among proteins displaying nominal regulation were fibulin-5 (p = 0.02), aquaporin-1 (p = 0.02) and prostacyclin synthase (p = 0.007). Cycloastragenol inhibits experimental abdominal aortic aneurysm progression. The suggested underlying mechanisms involve decreased matrix metalloprotease-2 activity and preservation of elastin and reduced calcification, thus, cycloastragenol could be considered for trial in abdominal aortic aneurysm patients.
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Project description:Analysis of differential gene expression for rutured vs stable abdominal aortic aneurysms (AAA) and for intermediate size (≤55mm) vs large (>70mm) AAA.
2018-02-27 | GSE98278 | GEO
Project description:In population-based studies performed on multiple continents during the past two decades, diabetes mellitus has been negatively associated with the prevalence and progression of abdominal aortic aneurysm (AAA) disease. We investigated the possibility that metformin, the primary oral hypoglycemic agent in use worldwide, may influence the progression of AAA disease.Preoperative AAA patients with diabetes were identified from an institutional database. After tabulation of individual cardiovascular and demographic risk factors and prescription drug regimens, odds ratios for categorical influences on annual AAA enlargement were calculated through nominal logistical regression. Experimental AAA modeling experiments were subsequently performed in normoglycemic mice to validate the database-derived observations as well as to suggest potential mechanisms of metformin-mediated aneurysm suppression.Fifty-eight patients met criteria for study inclusion. Of 11 distinct classes of medication considered, only metformin use was negatively associated with AAA enlargement. This association remained significant after controlling for gender, age, cigarette smoking status, and obesity. The median enlargement rate in AAA patients not taking oral diabetic medication was 1.5 mm/y; by nominal logistic regression, metformin, hyperlipidemia, and age ?70 years were associated with below-median enlargement, whereas sulfonylurea therapy, initial aortic diameter ?40 mm, and statin use were associated with above-median enlargement. In experimental modeling, metformin dramatically suppressed the formation and progression, with medial elastin and smooth muscle preservation and reduced aortic mural macrophage, CD8 T cell, and neovessel density.Epidemiologic evidence of AAA suppression in diabetes may be attributable to concurrent therapy with the oral hypoglycemic agent metformin.
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Project description:ImportancePreclinical studies suggest a potential role for aspirin in slowing abdominal aortic aneurysm (AAA) progression and preventing rupture. Evidence on the clinical benefit of aspirin in AAA from human studies is lacking.ObjectiveTo investigate the association of aspirin use with aneurysm progression and long-term clinical outcomes in patients with AAA.Design, setting, and participantsThis was a retrospective, single-center cohort study. Adult patients with at least 2 available vascular ultrasounds at the Cleveland Clinic were included, and patients with history of aneurysm repair, dissection, or rupture were excluded. All patients were followed up for 10 years. Data were analyzed from May 2022 to July 2023.Main outcomes and measuresClinical outcomes were time-to-first occurrence of all-cause mortality, major bleeding, or composite of dissection, rupture, and repair. Multivariable-adjusted Cox proportional-hazard regression was used to estimate hazard ratios (HR) for all-cause mortality, and subhazard ratios competing-risk regression using Fine and Gray proportional subhazards regression was used for major bleeding and composite outcome. Aneurysm progression was assessed by comparing the mean annualized change of aneurysm diameter using multivariable-adjusted linear regression and comparing the odds of having rapid progression (annual diameter change >0.5 cm per year) using logistic regression.ResultsA total of 3435 patients (mean [SD] age 73.7 [9.0] years; 2672 male patients [77.5%]; 120 Asian, Hispanic, American Indian, or Pacific Islander patients [3.4%]; 255 Black patients [7.4%]; 3060 White patients [89.0%]; and median [IQR] follow-up, 4.9 [2.5-7.5] years) were included in the final analyses, of which 2150 (63%) were verified to be taking aspirin by prescription. Patients taking aspirin had a slower mean (SD) annualized change in aneurysm diameter (2.8 [3.0] vs 3.8 [4.2] mm per year; P = .001) and lower odds of having rapid aneurysm progression compared with patients not taking aspirin (adjusted odds ratio, 0.64; 95% CI, 0.49-0.89; P = .002). Aspirin use was not associated with risk of all-cause mortality (adjusted HR [aHR], 0.92; 95% CI, 0.79-1.07; P = .32), nor was aspirin use associated with major bleeding (aHR, 0.88; 95% CI, 0.76-1.03; P = .12), or composite outcome (aHR, 1.16; 95% CI, 0.93-1.45; P = .09) at 10 years.ConclusionsIn this retrospective study of a clinical cohort of 3435 patients with objectively measured changes in aortic aneurysm growth, aspirin use was significantly associated with slower progression of AAA with a favorable safety profile.
| S-EPMC10716735 | biostudies-literature