scholarly journals Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model

2020 ◽  
Vol 134 (18) ◽  
pp. 2521-2534 ◽  
Author(s):  
Vianne Nsengiyumva ◽  
Smriti M. Krishna ◽  
Corey S. Moran ◽  
Joseph V. Moxon ◽  
Susan K. Morton ◽  
...  
Keyword(s):  
Vitamin D ◽  
Extracellular Matrix ◽  
Mouse Model ◽  
Vitamin D Deficiency ◽  
Ex Vivo ◽  
Aortic Aneurysms ◽  
Matrix Metalloproteinase 2 ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Abdominal Aortic

Abstract Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

scholarly journals Precision-Cut Kidney Slices as a Tool to Understand the Dynamics of Extracellular Matrix Remodeling in Renal Fibrosis

2016 ◽  
Vol 11 ◽  
pp. BMI.S38439 ◽  
Author(s):  
Federica Genovese ◽  
Zsolt S. Kàrpàti ◽  
Signe H. Nielsen ◽  
Morten A. Karsdal
Keyword(s):  
Extracellular Matrix ◽  
Collagen Type ◽  
Interstitial Fibrosis ◽  
Ex Vivo ◽  
Collagen Type I ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Renal Interstitial Fibrosis ◽  
Ex Vivo Model

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) surgery of the right ureter. The left kidney (contralateral) was used as internal control. Six rats were sham operated and used as the control group. Rats were terminated two weeks after the surgery; the kidneys were excised and precision-cut kidney slices (PCKSs) were cultured for five days in serum-free medium. Markers of collagen type I formation (P1NP), collagen type I and III degradation (C1M and C3M), and α-smooth muscle actin (αSMA) were measured in the PCKS supernatants by enzyme-linked immunosorbent assay. P1NP, C1M, C3M, and α-SMA were increased up to 2- to 13-fold in supernatants of tissue slices from the UUO-ligated kidneys compared with the contralateral kidneys ( P < 0.001) and with the kidneys of sham-operated animals ( P < 0.0001). The markers could also reflect the level of fibrosis in different animals. The UUO PCKS ex vivo model provides a valuable translational tool for investigating the extracellular matrix remodeling associated with renal interstitial fibrosis.

scholarly journals Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

2015 ◽  
Vol 308 (11) ◽  
pp. H1391-H1401 ◽  
Author(s):  
Santhosh K. Mani ◽  
Christine B. Kern ◽  
Denise Kimbrough ◽  
Benjamin Addy ◽  
Harinath Kasiganesan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Left Ventricular ◽  
Class I ◽  
Matrix Metalloproteinase 2 ◽  
Lv Function ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Lv Remodeling

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

scholarly journals Moderate aerobic exercise prevents matrix degradation and death in a mouse model of aortic dissection and aneurysm

2021 ◽  
Vol 320 (5) ◽  
pp. H1786-H1801
Author(s):  
Brittany O. Aicher ◽  
Jackie Zhang ◽  
Selen C. Muratoglu ◽  
Rebeca Galisteo ◽  
Allison L. Arai ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Mouse Model ◽  
Aerobic Exercise ◽  
Thoracic Aortic Aneurysm ◽  
Lysyl Oxidase ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Matrix Degradation ◽  
Aortic Aneurysm And Dissection ◽  
Oxidase Inhibition

Moderate aerobic exercise was shown to significantly reduce mortality, extracellular matrix degradation, and thoracic aortic aneurysm and dissection formation associated with lysyl oxidase inhibition in a mouse model. Gene expression suggested a reversal of TGF-β, inflammation, and extracellular matrix remodeling pathway dysregulation, along with augmented elastogenesis with exercise.

Abstract 195: Sulforaphane Protects Against Subarachnoid Hemorrhage and Alters the Expression of Inflammatory and Extracellular Matrix Remodeling Genes in a Mouse Model of Intracranial Aneurysm

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Crissey L Pascale ◽  
David M Sawyer ◽  
Lauren A Pace ◽  
Brannan E O’Neill ◽  
Devon O’Donnell ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Subarachnoid Hemorrhage ◽  
Treatment Group ◽  
Mouse Model ◽  
Intracranial Aneurysm ◽  
Lower Incidence ◽  
Control Group ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Rt Pcr

Introduction: Oxidative stress has been shown to play an important role in the pathogenesis of intracranial aneurysm (IA). Sulforaphane is an isothiocyanate that exhibits antioxidant properties via the Nrf2 transcription factor. We tested whether sulforaphane would protect against IA formation and subarachnoid hemorrhage (SAH) in a mouse model. Methods: C57BL/6 mice were treated intraperitoneally with either 0.5mg/kg/day of sulforaphane (treatment group, n = 32) or a vehicle solution (control group, n = 26) prior to being subjected to a well-established IA induction protocol involving unilateral nephrectomy, mineralocorticoid administration, and intracranial injection of elastase. Sulforaphane/vehicle treatments were begun seven days prior to elastase injection, and continued daily for the duration of the experiment. Animals were followed for 14 days until sacrifice, with measurement of the number of aneurysms formed and ruptured in each animal. Intracranial vessel tissue was collected, pooled, and analyzed using real-time PCR (RT-PCR) with experiments performed in triplicate (n = 3). Results: There was a lower incidence of IA in the treatment group (1.06 +/- 0.24 per animal) than in the control group (1.54 +/- 0.33), but this trend did not reach significance. The incidence of SAH in the treatment group (0.53 +/- 0.09 per animal) was approximately 50% lower than in the control group (1.08 +/- 0.21, p = 0.012). RT-PCR showed significant (p < 0.05) differences in the expression of interferon gamma, matrix metalloproteinase 9, collagen Ia2, interleukin-6, myosin heavy chain, and SM22 between the treatment and control groups. Conclusions: Treatment with sulforaphane resulted in a significantly lower incidence of SAH in a mouse model of IA. The expression of genes involved in inflammation and extracellular matrix remodeling were altered by sulforaphane administration.

Abstract P110: Proteomics Identified Novel Proteins Associated With Genetic Risk Of Abdominal Aortic Aneurysm: The Atherosclerosis Risk In Communities Study (ARIC)

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Brian Steffen ◽  
James S Pankow ◽  
Nathan Pankratz ◽  
Pamela L Lutsey ◽  
Faye L Norby ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Genetic Risk ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Related Protein ◽  
Kit Ligand ◽  
Risk Variants ◽  
Genome Wide ◽  
Abdominal Aortic ◽  
Complement C1q

Introduction: Abdominal aortic aneurysm (AAA) is a condition characterized by a weakened dilated vessel wall with the potential for lethal rupture. A recent genome-wide association study identified and replicated nine AAA-related variants (rs602633, rs4129267, rs3827066, rs1795061, rs10757274, rs10985349, rs9316871, rs6511720, and rs2836411), but pathways through which these loci may influence disease have not been elucidated. Hypothesis: AAA risk variants were hypothesized to be associated with plasma proteins with numerous roles including, but not limited to, inflammation and extracellular matrix remodeling. Methods: Data from participants of the community-based ARIC Study were used. Genomic DNA from whole blood was genotyped using the Affymetrix Genome-Wide Human SNP array 6.0. Concentrations of 4,870 proteins were determined using the SomaLogic aptamer-based capture array in plasma collected at visit 3 (1993-95). Outliers that were 6 standard deviations from the means were excluded. Race-specific multiple linear regression analysis evaluated associations between genetic variants and log base 2 transformed protein levels, with adjustment for age, sex, estimated glomerular filtration rate, field center, and ten principal components of ancestry. Identified proteins in whites (N=7,241) were then examined for replication in Black participants (N=1,671). Cox regression was used to evaluate the associations between identified proteins and incident AAA (n=454) over a median 21.2-year follow-up in all 11,064 participants. Results: In white participants twenty-six protein associations were identified for rs602633 ( PSRC1-CELSR2-SORT1 ), rs4129267 ( IL6R ), and rs3827066 ( PCIF1-ZNF335-MMP9 ) following Bonferroni correction ( p ≤5.13x10 -6 ). Associations were observed between rs4129267 and soluble interleukin-6 receptor subunit alpha (β=-0.339; p<1.0E-200) and CRP (β=0.093; p=2.24E-7); rs602633 and granulin (β=0.184; p<1.0E-200), complement C1q TNF-related protein-1 (β=0.115; p=2.17E-184), and neogenin (β=-0.031; p=5.60E-13); and rs3827066 and kit ligand (β=-0.045; p=2.41E-08). Five associations were replicated in Black participants ( p ≤1.9x10 -3 ). In the whole cohort, top quintiles of CRP (HR: 1.68; 95% CI: 1.22, 2.31), kit ligand (HR: 0.56; 95% CI: 0.40, 0.78) and neogenin (HR: 0.57 95% CI: 0.42, 0.78) were significantly related to incident AAA risk compared to corresponding bottom quintiles. Conclusions: Three of the nine AAA risk variants were associated with plasma protein concentrations, with the strongest associations for those involved in inflammation, endothelial dysfunction, and extracellular matrix remodeling. Granulin, complement C1q tumor necrosis factor-related protein-1, kit ligand, and neogenin represent novel targets for genetic risk of AAA and may link genetic susceptibility to disease pathogenesis.

scholarly journals Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm

2012 ◽  
Vol 55 (1) ◽  
pp. 171-179.e2 ◽  
Author(s):  
Claudia Saracini ◽  
Paola Bolli ◽  
Elena Sticchi ◽  
Giovanni Pratesi ◽  
Raffaele Pulli ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Abdominal Aortic

Quantification of fibronectin as a method to assess ex vivo extracellular matrix remodeling

2016 ◽  
Vol 478 (2) ◽  
pp. 586-591 ◽  
Author(s):  
C.L. Bager ◽  
N. Gudmann ◽  
N. Willumsen ◽  
D.J. Leeming ◽  
M.A. Karsdal ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Ex Vivo ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling
Sign in / Sign up

Export Citation Format

Share Document