Relaxin reverses inflammatory and immune signals in aged hearts
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA416509 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6239820_1.fastq.gz | Fastqsanger.gz | |||
| SRR6239820_2.fastq.gz | Fastqsanger.gz | |||
| SRR6239830_1.fastq.gz | Fastqsanger.gz | |||
| SRR6239830_2.fastq.gz | Fastqsanger.gz | |||
| SRR6239821_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: ‘Healthy’ aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in recent clinical trials, Relaxin-therapy for 2-days could reduce mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin’s short life-span (hours) but long-lasting protective actions led us to test the hypothesis that relaxin acts at a genomic level to reverse maladaptive remodeling in aging and HF. Methods and Results: Young (9-month) and aged (24-month), male and female F-344/Brown Norway rats were treated with relaxin (0.4 mg/kg/day) for 2-weeks delivered by subcutaneous osmotic mini-pumps or with sodium acetate (controls). The genomic effects of aging and relaxin were evaluated by extracting RNA from the left ventricles and analyzing genomic changes by RNA-sequencing, Ingenuity Pathway Analysis, MetaCore and tissue immunohistochemistry. We found that aging promotes a native inflammatory response with distinct sex-differences and relaxin suppresses transcription of multiple genes and signaling pathways associated with inflammation and HF in both genders. In addition, aging significantly increased macrophage infiltration in the ventricles and activation of the complement cascade, and relaxin reversed these age-related effects. Conclusion: These data support the hypothesis that relaxin alters gene transcription and suppresses inflammatory pathways and genes associated with HF and aging. Relaxin’s suppression of inflammation and fibrosis supports its potential as a therapy for cardiovascular and inflammation-related diseases, such as HF, AF and diabetes.
2018-01-04 | GSE106377 | GEO
Project description:BACKGROUND:'Healthy' aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in recent clinical trials, Relaxin-therapy for 2-days could reduce mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin's short life-span (hours) but long-lasting protective actions led us to test the hypothesis that relaxin acts at a genomic level to reverse maladaptive remodeling in aging and HF. METHODS AND RESULTS:Young (9-month) and aged (24-month), male and female F-344/Brown Norway rats were treated with relaxin (0.4 mg/kg/day) for 2-weeks delivered by subcutaneous osmotic mini-pumps or with sodium acetate (controls). The genomic effects of aging and relaxin were evaluated by extracting RNA from the left ventricles and analyzing genomic changes by RNA-sequencing, Ingenuity Pathway Analysis, MetaCore and tissue immunohistochemistry. We found that aging promotes a native inflammatory response with distinct sex-differences and relaxin suppresses transcription of multiple genes and signaling pathways associated with inflammation and HF in both genders. In addition, aging significantly increased: macrophage infiltration and atrial natriuretic peptide levels in female ventricles, and activation of the complement cascade, whereas relaxin reversed these age-related effects. CONCLUSION:These data support the hypothesis that relaxin alters gene transcription and suppresses inflammatory pathways and genes associated with HF and aging. Relaxin's suppression of inflammation and fibrosis supports its potential as a therapy for cardiovascular and inflammation-related diseases, such as HF, AF and diabetes.
| S-EPMC5773192 | biostudies-literature
Project description:Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function in 24 mo. mice. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.
2020-07-23 | PXD018545 | Pride
Project description:The relaxin-RXFP1 signaling loop promotes survival and proliferation in a panel of high-grade serous ovarian (HGSOC) cancer cell lines. Knockdown of either the relaxin receptor-1(RXFP1) or relaxin-2 (RLN2) decreased growth and tumorigenicity and increased apoptosis in dependent HGSOC cell lines. Transcriptome profiling of relaxin-dependent HGSOC cells using RNA-Seq revealed genes with altered expression levels following relaxin treatment. This included components of the Notch signaling pathway (NOTCH1 and NOTCH3), Wnt signaling (DVL1, LRP5, BCL9) and extracellular matrix regulation (VEGF-A, MMP9, MMP23). Collectively, genes and pathways upregulated by relaxin provide insight into the mechanisms by which it sustains proliferation of dependent cells.
2020-12-31 | GSE151280 | GEO
Project description:Nicotinamide mononucleotide supplementation reverses the declining quality of maternally aged oocytes
| PRJNA644537 | ENA
Project description:Healthy aging results in cardiac structural and electrical remodeling that increases susceptibility to cardiovascular diseases. Relaxin, an insulin-like hormone, suppresses atrial fibrillation, inflammation and fibrosis in aged rats but the mechanisms-of-action are unknown. Here we show that relaxin treatment of aged rats reverses pathological electrical remodeling (increasing Nav1.5 expression and localization of Connexin43 to intercalated disks) by activating canonical Wnt signaling. In isolated adult ventricular myocytes, relaxin upregulated Nav1.5 (EC50 = 1.3 nM) by a mechanism inhibited by the addition of Dickkopf-1. Furthermore, relaxin increased the levels of connexin43, Wnt1, and cytosolic and nuclear β-catenin. Treatment with Wnt1 or CHIR-99021 (a GSK3β inhibitor) mimicked the relaxin effects. In isolated fibroblasts, relaxin blocked TGFβ-induced collagen elevation in a Wnt dependent manner. These findings demonstrate a close interplay between relaxin and Wnt-signaling resulting in myocardial remodeling and reveals a fundamental mechanism of great therapeutic potential.
| S-EPMC6897890 | biostudies-literature
Project description:We developed immunoaffinity-selected reaction monitoring assays for the measurment of human relaxin-1 and relaxin-2 proteins in biological and clinical samples.
2024-07-04 | PXD051230 | Pride
Project description:MicroRNAs have been reported to be involved in the regulation of cellular and organismal aging. However, little is known about the role of microRNAs in cardiac aging. We used microarrays to examine microRNA profiles in the hearts from young (8 week-old) and middle-aged (15 month-old) male mice.
2019-06-14 | GSE83329 | GEO
Project description:This experiment aimed to investigate the transcriptional role of G4 resolvase Dhx36 in the adult mouse heart. We compared three pools of wild-type (WT) mouse hearts with three pools of Dhx36 conditional knockout (cKO) hearts. In the mutant mice, Dhx36 was conditionally deleted in cardiomyocytes using the Myh6-cre transgenic line. Each of the six pools was created using RNA extracted from 3-5 hearts from mice aged approximately 21 days. The cKO mice developed dilated cardiomyopathy and began experiencing sudden death at 40 days old, with no mutants surviving beyond 5 months.
2024-09-15 | E-MTAB-14440 | biostudies-arrayexpress
Project description:Hearts from young (2-4 month) and moderately aged (16-18 month) C57/Bl6 male mice were subjected to i) 20 min global ischaemia, 60 min reperfusion or ii) 80 min aerobic perfusion/normoxia.
2005-12-31 | E-MEXP-496 | biostudies-arrayexpress