Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cx43 in Cdh5+ cells maintains blood-brain barrier integrity by NAD+ during aging

ABSTRACT: Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in Cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3. CX43 interacts with and negatively regulates poly (ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway’s role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.

ORGANISM(S): Mus musculus

PROVIDER: GSE172382 | GEO | 2021/04/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Cx43 in Cdh5+ cells maintains blood-brain barrier integrity by NAD+ during aging

Project description:Cx43 in Cdh5+ cells maintains blood-brain barrier integrity by NAD+ during aging

| PRJNA723191 | ENA

CX43 heterozygous, Cx43 null and Cx32 null vs wildtype neonatal mouse brain

Project description:Cy3-labeled cDNA from brains of neonatal C57BL Cx43 null, Cx43 heterozygous and Cx32 null mice were compared among themselves and to Cy3-labeled cDNA from brains of neonatal C57BL wildtype mice through Cy5-labeled sample reference prepared at once for the entire experiment from aorta, brain, heart, kidney, liver, lung, ovary/testicles, spleen, and stomach - equal amounts from adult male and female C57BL mice.

2010-06-05 | E-GEOD-1954 | biostudies-arrayexpress

CX43 heterozygous, Cx43 null and Cx32 null vs wildtype neonatal mouse brain

2004-11-12 | GSE1954 | GEO

Cx43-interaction network in the heart

Project description:The main objective of the present report was to unravel the Cx43-interaction network in the heart, and to establish the impact of heart ischemia and I/R upon these interactions. In order to characterize the cardiac Cx43 interactome under ischemia and I/R, a quantitative proteomic analysis was performed, through the combination of immunopurification of endogenous Cx43 (Cx43 IP) and identification of its binding partners with the SWATH-MS approach, using rat hearts maintained in a Langendorff apparatus. In the present approach 444 proteins were identified, including proteins identified based on a single peptide (supplementary table I). From these 444 proteins, 299 (approximately 67 % of the entire dataset) were quantified and compared between the various experimental conditions (including non-specific binding to control IP samples). These 299 proteins were further evaluated by a series of complementary analysis to deciphering the truly interactors of Cx43. According with this evaluation, 236 out of the 299 quantified proteins were considered as putative Cx43 interacting partners in the cardiac context presented The results obtained in this study demonstrate that Cx43 mainly interacts with proteins related with metabolism, signaling and trafficking, and that this interactome can be differentially modulated in diseased hearts. Our results shed new light upon the understanding of Cx43 functions in the heart, both in health and disease, which ultimately may lead to the establishment of new therapeutic targets to modulate cardiac homeostasis.

2015-09-09 | PXD002331 | Pride

CX43 KO vs WT cortical astrocytes

Project description:RNA samples extracted from astrocytes cultured from wild type and Cx43 null neonatal mice were dye labeled and individually co-hybridized with a reference of labeled cDNAs pooled from a variety of tissues on eight gene arrays containing 8975 mouse DNA sequences

2010-06-05 | E-GEOD-580 | biostudies-arrayexpress

CX43 KO vs WT cortical astrocytes

2003-08-06 | GSE580 | GEO

“Compensatory” transcriptional mechanisms: Comparison of transcriptomes of Cx43 null and knockdown astrocytes

Project description:Our previous studies on brains and hearts of Cx null mice have revealed that expression level, control and coordination of a very large number of genes are regulated compared to wildtype littermates. This result suggests the possibility that the phenotype of the Cx null animals may include genes not only linked to the intracellular communication that gap junction channels provide but also to genes with very different functions. The question often arises, however, of the degree to which “compensation” occurs in knockouts such that gene regulation depends on pathways altered to make up for the missing gene rather than reflecting normal gene interlinkage. In order to explore this question in the Cx43 null setting, we have compared gene expression patterns in Cx43 null astrocytes with that in wildtype astrocytes acutely treated (36 hrs) with Cx43 siRNA. In these studies, Cx43 levels determined by Western blot analysis were reduced by at least 70% following siRNA treatment, comparable with the 3.24x downregulation for mRNA. For each group of astrocytes, four independent cultures were compared, using oligonucleotide microarrays printed with the mouse Qiagen library. 8060 well annotated unigenes were identifiable in all 8 arrays; of these, 8.2% were upregulated and 6.0% downregulated in Cx43 null astrocytes and 6.2% upreguated and 7.0 downregulated in siRNA treated astrocytes. Interestingly, regulation of 92.3% unigenes significantly regulated in both Cx43 deficient astrocytes had the same orientation, representing a highly significant overlap of gene expression alteration. These experiments thus indicate that the gene regulation in Cx43 null astrocytes is largely due to direct interlinkage rather than to developmental compensation for the missing gene. Keywords: genetic modification

2007-06-20 | GSE8168 | GEO

Mitochondrial PARP1 Regulates NAD+-dependent Poly ADP-ribosylation on Mitochondrial Nucleoids

Project description:Poly ADP-ribose (PAR) polymerases (PARPs) play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and PARylation. The existence of mtPARP is controversial, and the biological roles for mtPARP induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induces PARylation which is suppressed by PARP inhibitor olaparib treatment. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA) labeling. To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) . We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and NAD+ dependent mtPARP1 activity contributes to mtDNA transcription regulation.

2022-08-20 | GSE182533 | GEO

Cx43 purified protein analysis (N-term analysis)

Project description:Purified Cx43 was analyzed to check for modifications of its N-terminus to aid structural studies.

2023-07-27 | PXD033824 | Pride

CDH2 and Cx43 knockdown CSCs compaired with scramble (control) in breast cancer

Project description:We report the gene expression changes in CDH2 and Cx43 knockdown CSCs as compaired to scramble (control) in MDA-MB-231

2021-05-27 | GSE138434 | GEO