Sclerostin Antibody Does Not Promote Atheroprogression, Plaque Mineralization, or Inflammation in Ovariectomized Apolipoprotein E–Deficient Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA542264 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9040130_1.fastq.gz | Fastqsanger.gz | |||
| SRR9040130_2.fastq.gz | Fastqsanger.gz | |||
| SRR9040140_1.fastq.gz | Fastqsanger.gz | |||
| SRR9040140_2.fastq.gz | Fastqsanger.gz | |||
| SRR9040150_1.fastq.gz | Fastqsanger.gz |
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Project description:Objective—Overexpression or administration of sclerostin has been reported to have atheroprotective and anti-inflammatory effects in apolipoprotein E knockout (ApoE KO) mice infused with angiotensin II; however, effects of sclerostin inhibition on these processes are not known. This study examined the effects of sclerostin inhibition with a sclerostin antibody on transcriptional changes in the aortic arch, associated morphological changes in aortic atherosclerotic plaques, and circulating markers of inflammation in ApoE KO ovariectomized (OVX) mice fed a high-fat diet. Approach and Results—Sclerostin antibody or vehicle was administered by subcutaneous injection once weekly for 3, 8, or 16 weeks to ApoE KO-OVX and wild-type-OVX mice fed a high-fat diet. As a comparator, alendronate or saline was administered twice weekly for 16 weeks to ApoE KO-OVX mice fed a high-fat diet. Sclerostin antibody had no effect on aortic total or mineralized plaque volume, determined by microcomputed tomography. Sclerostin antibody had no meaningful effects on plaque histopathology or systemic markers of inflammation or endothelial/platelet activation. Transcriptional analysis of the aortic arch revealed significant gene expression and signaling pathway changes in ApoE KO mice compared with wild-type, consistent with the genotype and atheroprogression, that were not affected by sclerostin antibody treatment. Alendronate treatment did not alter plaque volume or histopathology. Conclusions—This study shows that inhibition of sclerostin by sclerostin antibody does not promote atheroprogression or affect systemic markers of inflammation in the high-fat diet ApoE KO-OVX mouse model and does not alter the expression of genes/pathways implicated in atherosclerosis.
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Project description:Rosiglitazone-targeted transcriptional networks as gene expression signature of physiological and pathological mineralization – a top-down approach to identify novel targets for bone and vascular health Clinical studies have recently revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. At the cellular level, we have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and apoptosis. In calcifying human vascular cells, rosiglitazone stimulates pathological mineralization, an effect that was diminished by the antioxidant resveratrol. In order to elucidate the transcriptional networks underlying the rosiglitazone-enhanced mineralization phenotype, we performed genome-wide transcriptional profiling of osteogenic hMSCs treated with rosiglitazone for short-term periods of 1 up to 48h during the first two days of culture time, a phase that we show is sufficient to mediate the stimulatory effect of rosiglitazone on mineralization. Microarray-based mRNA expression analysis revealed 190 probes that were differently expressed in at least one condition compared to vehicle-treated control. This rosiglitazone gene signature contained confirmed primary PPAR targets and was also endogenously regulated during osteogenic differentiation from hMSCs and osteoblast-like differentiation of vascular smooth muscle cells (VSMCs) into calcifying vascular cells (CVCs). Further comparative analysis revealed rosiglitazone targets that were commonly enriched in osteoblasts and CVCs or specifically enriched in either osteoblasts or CVCs. Finally, we compared the expression patterns of CVC-specific genes with patient expression data from carotid plaque versus intact adjacent tissue, and identified five rosiglitazone targets that were differentially regulated in CVCs and carotid plaque but not osteoblasts when compared to their respective non-mineralizing counterparts. These targets, i.e PDK4, SDC4, SPRY4, TCF4, and DACT1 may specifically control extracellular matrix mineralization in vascular cells and hence provide interesting candidates for further investigations to improve vascular health.
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Project description:Ten-week-old male C57/bl6 mice were treated with a sclerostin-inhibiting antibody or vehicle for 2 weeks. Tibial diaphyses were removed, bone marrow flushed and total RNA was isolated for RNA-sequencing.
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Project description:Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extra-cardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and maintenance remains poorly understood. We compared the transcriptome of CHD tissues from 49 T21 and 226 euploid (eCHD) patients. We resolved cell lineages that mis-expressed T21 transcripts by cardiac single-nucleus RNA-sequencing and RNA in situ hybridization. Compared to eCHD, T21 had increased chr21 gene expression, 11-fold greater levels (p=1.2E-8) of SOST (chr17), encoding the Wnt-inhibitor sclerostin, and 1.4-fold higher levels (p=8.7E-8) of the SOST transcriptional activator ZNF467 (chr7). Cardiac endothelial cells co-expressed SOST and ZNF467. T21 endothelial cells had 6.9-fold higher SOST (p=2.7E-27) with downregulation of Wnt pathway genes. Within the chr21 CHD critical region, the expression of DSCAM was correlated with SOST (p=1.9E-5) and ZNF467 (p=2.9E-4). Deletion of DSCAM in T21 endothelial cells derived from human induced pluripotent stem cells resulted in decreased sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we conclude that T21-mediated increased sclerostin levels inappropriately inhibits Wnt activities and promotes Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.
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