Abstract 632: Aortic Dilatation in Marfan Syndrome: A Result of Amplification of Molecular Mechanisms of Aging?

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Michael A Hagler ◽  
Grace Casaclang-Verzosa ◽  
Bin Zhang ◽  
Carolyn Roos ◽  
Nassir Thalji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Expression Patterns ◽  
Mutant Mice ◽  
Aortic Dilatation ◽  
Mrna Levels ◽  
Wild Type ◽  
Fibrillin 1 ◽  
Tgf Β1

Marfan syndrome (MFS) is a genetic disease with a mutation for the microfibrillar constituent protein fibrillin-1 being the most prevalent. MFS is often associated with progressive aortic root dilation, ultimately progressing to aortic aneurysm and dissection. While recent work has shown that increased angiotensin-II receptor type-1 and transforming growth factor beta (TGF-β) signaling contributes to aneurysm formation in aorta, efficacious therapeutic targets remain elusive. Given previous reports of progeriod phenotypes in a subset of Marfan patients, we sought to determine whether there are molecular changes that are consistent with accelerated aging in a mouse model of Marfan syndrome. In mice carrying a loss-of-function mutation in fibrillin-1, we assessed aortic root dimensions by echocardiography and gene expression levels of TGF-β1-3, runt related transcription factor 2 (RUNX2), and the cellular senescent marker CDKN2A by quantitative real time PCR at 3 and 14 months of age. As expected, aortic sinus dimensions did not change significantly with aging in wild type mice, but increased dramatically in fibrillin-1 mutant mice compared to wild-type littermate controls and with age (p < 0.05 for both). TGF-β1 ligand expression paralleled age and disease-dependent changes in aortic dimensions, however TGF-β2 and TGF-β3 mRNA levels did not. Aortic dilatation was associated with increased gene expression of RUNX2 with aging and in marfanoid mice. Interestingly, fibrillin-1 mutant mice demonstrated marked increases in expression of the anti-proliferative cell-cycle checkpoint protein CDKN2A at both time points, and correlated with changes in TGF-β1 (R 2 =0.54) and RUNX2 (R 2 =0.69) mRNA. CDNK2A gene expression patterns, however, demonstrated a poor correlation with expression of TGF-β2 and TGF-β3 (R 2 =0.04 and 0.06. respectively). Collectively, these data lend insight into novel mechanisms that may regulate development of aortic root dilation in patients MFS and are the first to implicate increased senescent cell burden in Marfan syndrome. Furthermore, we propose that clearance of senescent cells could be a viable therapeutic intervention to slow progression aortic root-dilation and aneurysm in patients with Marfan syndrome.

Abstract 2959: TGF-beta Is A Promising Biomarker For Monitoring The Aortic Root Dilatation And Losartan Therapy In Marfan Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Peter Matt ◽  
Jennifer Habashi ◽  
Tammy Holm ◽  
Erin Klein ◽  
Matt Gamradt ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Aortic Root ◽  
Serum Levels ◽  
Serum Concentrations ◽  
Tgf Beta ◽  
Wild Type ◽  
Serum Samples ◽  
Total Acid ◽  
Fibrillin 1 ◽  
Aortic Root Dilatation

Objectives: Aortic root dilatation is the main cause of morbidity and mortality in Marfan syndrome (MFS), a disorder caused by mutations in the gene encoding fibrillin-1 and consequent dysregulation of TGF-beta signaling. The aim of this study was to discover a serological biomarker for the aortic root dilatation in a mouse model of MFS, that was also responsive to losartan therapy. Methods: Serum samples from mice heterozygous for a fibrillin-1 missense mutation (C1039G/+) and wild-type mice treated with losartan or placebo were obtained at 10 weeks, 6 months and 10 months of age. Total (acid activated) TGF-beta 1 serum concentrations were measured by ELISA. Echo measurements of the aortic root were obtained from a parasternal long axis view at 10 months of age. Results: Mean TGF-beta serum concentrations were higher in C1039G/+ mice compared to wild-type mice (p=0.01; 80.0 ng/ml (n=5) vs. 58.3 ng/ml (n=4) at 10 weeks, 117.4 ng/ml (n=11) vs. 87.0 ng/ml (n=6) at 6 months, 137.5 ng/ml (n=3) vs. 103.0 ng/ml (n=2) at 10 months, respectively). Losartan-treated C1039G/+ mice had significantly lower mean TGF-beta serum levels compared to C1039G/+ mice with placebo (p=0.007; 92.9 ng/ml (n=5) vs. 117.4 ng/ml (n=11) at 6 months, 101.2 ng/ml (n=13) vs. 137.5 ng/ml (n=3) at 10 months, respectively). Mean TGF-beta serum concentrations in losartan-treated C1039G/+ mice and wild-type mice with placebo were not significant different (p=0.3; 92.9 ng/ml (n=5) vs. 87.0 ng/ml (n=6) at 6 months, 101.2 ng/ml (n=13) vs. 103.0 ng/ml (n=2) at 10 months, respectively). Echo analyses revealed significantly smaller mean aortic root diameters in 10 months old wild-type and losartan-treated C1039G/+ mice compared to age-matched C1039G/+ mice with placebo (p=0.001; 1.94 mm (n=2) and 2.06 mm (n=13) vs. 2.4 mm (n=3), respectively). Conclusions: TGF-beta serum levels are higher in C1039G/+ mice compared to wild-type mice. Losartan treatment of C1039G/+ mice reduces TGF-beta serum concentrations and aortic root diameters towards wild-type levels. Serum TGF-beta is a promising biomarker for prognostication and monitoring the therapeutic response to losartan therapy in Marfan syndrome.

Gene expression analysis of the pro-oestrous-stage rat uterus reveals neuroligin 2 as a novel steroid-regulated gene

2004 ◽  
Vol 16 (8) ◽  
pp. 763 ◽  
Author(s):  
Han-Seung Kang ◽  
Chae-Kwan Lee ◽  
Ju-Ran Kim ◽  
Seong-Jin Yu ◽  
Sung-Goo Kang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Northern Blot ◽  
Blot Analysis ◽  
Northern Blot Analysis ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Oestrous Cycle ◽  
Mrna Levels ◽  
Rat Uterus ◽  
Ovx Rats

In the present study, differential gene expression in the uteri of ovariectomised (OVX) and pro-oestrous rats (OVX v. pro-oestrus pair) was investigated using cDNA expression array analysis. Differential uterine gene expression in OVX rats and progesterone (P4)-injected OVX rats (OVX v. OVX + P4 pair) was also examined. The uterine gene expression profiles of these two sets of animals were also compared for the effects of P4 treatment. RNA samples were extracted from uterine tissues and reverse transcribed in the presence of [α32P]-dATP. Membrane sets of rat arrays were hybridised with cDNA probe sets. Northern blot analysis was used to validate the relative gene expression patterns obtained from the cDNA array. Of the 1176 cDNAs examined, 23 genes showed significant (>two-fold) changes in expression in the OVX v. pro-oestrus pair. Twenty of these genes were upregulated during pro-oestrus compared with their expression in the OVX rat uterus. In the OVX v. OVX + P4 pair, 22 genes showed significant (>two-fold) changes in gene expression. Twenty of these genes were upregulated in the OVX + P4 animals. The genes for nuclear factor I–XI, afadin, neuroligin 2, semaphorin Z, calpain 4, cyclase-associated protein homologue, thymosin β-4X and p8 were significantly upregulated in the uteri of the pro-oestrus and OVX + P4 rats of both experimental pairs compared with the OVX rat uteri. These genes appear to be under the control of P4. One of the most interesting findings of the present study is the unexpected and marked expression of the neuroligin 2 gene in the rat uterus. This gene is expressed at high levels in the central nervous system and acts as a nerve cell adhesion factor. According to Northern blot analysis, neuroligin 2 gene expression was higher during the pro-oestrus and metoestrus stages than during the oestrus and dioestrus stages of the oestrous cycle. In addition, neuroligin 2 mRNA levels were increased by both 17β-oestradiol (E2) and P4, although P4 administration upregulated gene expression to a greater extent than injection of E2. These results indicate that neuroligin 2 gene expression in the rat uterus is under the control of both E2 and P4, which are secreted periodically during the oestrous cycle.

scholarly journals GDF-9 and BMP-15 mRNA Levels in Canine Cumulus Cells Related to Cumulus Expansion and the Maturation Process

Animals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 462 ◽  
Author(s):  
George Ramirez ◽  
Jaime Palomino ◽  
Karla Aspee ◽  
Monica De los Reyes
Keyword(s):  
Gene Expression ◽  
Estrous Cycle ◽  
Expression Patterns ◽  
Cumulus Cells ◽  
Mrna Levels ◽  
Cumulus Expansion ◽  
Polymerase Chain ◽  
Specific Regulation ◽  
Reproductive Phases

The competence to undergo expansion is a characteristic of cumulus cells (CCs). The aim was to investigate the expression of GDF-9 and BMP-15 mRNA in canine cumulus cells in relation to cumulus expansion and meiotic development over the estrous cycle. CCs were recovered from nonmatured and in vitro-matured (IVM) dog cumulus oocyte complexes (COCs), which were obtained from antral follicles at different phases of the estrous cycle. Quantitative real-time polymerase chain reaction (q-PCR) was used to evaluate the relative abundance of GDF-9 and BMP-15 transcripts from the CCs with or without signs of expansion. The results were evaluated by ANOVA and logistic regression. The maturity of the oocyte and the expansion process affected the mRNA levels in CCs. There were differences (p < 0.05) in GDF-9 and BMP-15 gene expression in CCs isolated from nonmatured COCs when comparing the reproductive phases. Lower mRNA levels (p < 0.05) were observed in anestrus and proestrus in comparison to those in estrus and diestrus. In contrast, when comparing GDF-9 mRNA levels in IVM COCs, no differences were found among the phases of the estrous cycle in expanded and nonexpanded CCs (p < 0.05). However, the highest (p < 0.05) BMP-15 gene expression in CCs that did not undergo expansion was exhibited in anestrus and the lowest (p < 0.05) expression was observed in estrus in expanded CCs. Although the stage of the estrous cycle did not affect the second metaphase (MII )rates, the expanded CCs obtained at estrus coexisted with higher percentages of MII (p < 0.05). In conclusion, the differential expression patterns of GDF-9 and BMP-15 mRNA transcripts might be related to cumulus expansion and maturation processes, suggesting specific regulation and temporal changes in their expression.

The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE–/– and Wild-Type Mice

Gerontology ◽  
2018 ◽  
Vol 65 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Bojana Jakic ◽  
Mattias Carlsson ◽  
Maja Buszko ◽  
Giuseppe Cappellano ◽  
Christian Ploner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Endurance Exercise ◽  
Transforming Growth Factor ◽  
Physical Endurance ◽  
Heat Shock Protein 60 ◽  
Wild Type ◽  
Aortic Lesion ◽  
Tgf Β1 ◽  
Aortic Lesions

Background: Atherosclerosis is the leading cause of death worldwide. The disease development is by and large driven by old age and lifestyle factors, such as diet, physical activity, and smoking. In the present study, we have investigated the effect of exercise and diet on the development of atherosclerosis in young and aged mice. Objective: This study aimed at comparing multiple age-dependent factors that may influence atherosclerosis in a transgenic mouse model. Methods: Young (14 weeks) and aged (49–52 weeks) C57BL/6 wild-type (WT) and atherosclerosis-prone ApoE–/– mice were subjected to physical endurance exercise on a treadmill, with or without a high-fat diet. Five weeks later, the frequencies of regulatory T cells (TREGs) in lymph nodes were assessed by flow cytometry, plasmatic cytokines (interleukin [IL]-1β, IL-6, IL-10, IL-17, interferon-γ, tumor necrosis factor-α, and transforming growth factor [TGF]-β1) levels were determined by Luminex assay. Lipids (cholesterol and triglycerides) and anti-heat shock protein 60 (HSP60) autoantibodies were measured by ELISA. Aortic lesion sizes were assessed by en face imaging. Microarray analysis and qPCR of skeletal muscle gene expression were also performed. Results: Exercise leads to a reduction of aortic lesions in young ApoE–/– and aged WT mice independent of diet. In most groups, this reduction was followed by an increased proportion of TREGs and TGF-β1 levels. Moreover, gene expression analysis showed that exercise seems to affect the AMPK signaling pathway. In particular, PGC-1α1 mRNA was induced in aged WT mice, whereas it was reduced in young ApoE–/– mice. In addition, GSEA analysis showed a marked reduction in the insulin signaling pathway in aged ApoE–/– mice. Conclusion: Practicing endurance exercise seems to be enough for reducing early aortic lesion formation, independent of diet. However, this was only true in mice with smaller aortic lesions, since mice with large, advanced, complicated atherosclerotic plaques did not show any reduction in lesion size with exercise training.

Abstract 1086: CTNNB1-mutated desmoid tumors have different gene expression patterns compared to wild-type ones

2015 ◽  
Author(s):  
Chiara Colombo ◽  
Loris De Cecco ◽  
Antonino Belfiore ◽  
Silvana Canevari ◽  
Marco Fiore ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Desmoid Tumors ◽  
Wild Type

scholarly journals Gene Expression Patterns Distinguish Mortality Risk in Patients with Postsurgical Shock

2020 ◽  
Vol 9 (5) ◽  
pp. 1276
Author(s):  
Pedro Martínez-Paz ◽  
Marta Aragón-Camino ◽  
Esther Gómez-Sánchez ◽  
Mario Lorenzo-López ◽  
Estefanía Gómez-Pesquera ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Mortality Risk ◽  
Validation Cohort ◽  
Expression Patterns ◽  
Gene Expression Signature ◽  
Mrna Levels ◽  
Characteristic Analysis ◽  
Discovery Cohort ◽  
Risk Of Death

Nowadays, mortality rates in intensive care units are the highest of all hospital units. However, there is not a reliable prognostic system to predict the likelihood of death in patients with postsurgical shock. Thus, the aim of the present work is to obtain a gene expression signature to distinguish the low and high risk of death in postsurgical shock patients. In this sense, mRNA levels were evaluated by microarray on a discovery cohort to select the most differentially expressed genes between surviving and non-surviving groups 30 days after the operation. Selected genes were evaluated by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort to validate the reliability of data. A receiver-operating characteristic analysis with the area under the curve was performed to quantify the sensitivity and specificity for gene expression levels, which were compared with predictions by established risk scales, such as acute physiology and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA). IL1R2, CD177, RETN, and OLFM4 genes were upregulated in the non-surviving group of the discovery cohort, and their predictive power was confirmed in the validation cohort. This work offers new biomarkers based on transcriptional patterns to classify the postsurgical shock patients according to low and high risk of death. The results present more accuracy than other mortality risk scores.

scholarly journals Expression of Inflammation-Related Genes Is Altered in Gastric Tissue of Patients with Advanced Stages of NAFLD

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Rohini Mehta ◽  
Aybike Birerdinc ◽  
Arpan Neupane ◽  
Amirhossein Shamsaddini ◽  
Arian Afendy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatic Fibrosis ◽  
Interleukin 1 ◽  
Expression Patterns ◽  
Interleukin 8 ◽  
Morbidly Obese ◽  
Low Grade ◽  
Mrna Levels ◽  
Gastric Tissue ◽  
Hepatic Inflammation

Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD.

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