Protein phosphatase 2A activation promotes heart transplant acceptance in mice
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ABSTRACT:
PROVIDER: PRJNA989246 | ENA |
REPOSITORIES: ENA
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Project description:Background: While heart transplantation is the standard treatment for heart failure, both acute and chronic transplant rejection frequently occur. Since the modulation of protein phosphatase PP2A activity is critical for tissue and organ homeostasis under physiological and pathophysiological conditions, PP2A may also affect the ability to tolerate transplanted organs. Here we demonstrate that administration of a novel class of small molecule activators of PP2A (SMAPs) prolonged cardiac allograft survival in a mouse heterotopic heart transplantation model. Mechanistically, SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNAseq data derived from Tregs of treated splenic tissue. Importantly, SMAPs further prolonged CTLA4-Ig (an immunosuppressive agent utilized in organ transplantation)-induced cardiac rejection tolerance and extended allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and smooth muscle cell proliferation. Mechanistic studies implicate SMAPs elicited suppression of MEK/ERK pathways as a unifying mechanism for the aforementioned effects in Tregs and SMCs. These findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation and add knowledge to the phosphatase driven regulation of the immune system in the context of organ transplantation.
2023-07-20 | GSE236206 | GEO
Project description:PBMC samples from heart transplant patients were profiled. Sample classification was based on endomyocardial biopsy at the time of sample collection. Keywords = Transplant Keywords = Transplantation Keywords = Heart Transplant Keywords = Graft Rejection Keywords = Rejection Keywords = PBMC Keywords = Immune Response Keywords = Peripheral Blood
2010-06-10 | E-GEOD-2445 | biostudies-arrayexpress
Project description:PBMC samples from heart transplant patients were profiled. Sample classification was based on endomyocardial biopsy at the time of sample collection. Keywords = Transplant Keywords = Transplantation Keywords = Heart Transplant Keywords = Graft Rejection Keywords = Rejection Keywords = PBMC Keywords = Immune Response Keywords = Peripheral Blood Keywords: other
2005-09-01 | GSE2445 | GEO
Project description:Combined heart-lung transplant for COVID-19
| PRJNA688216 | ENA
Project description:As a serine/threonine phosphatase, protein phosphatase 2A (PP2A) is essential in numerous physiological processes. Our previously study confirmed PP2A dysfunction can cause azoospermia by generating catalytic subunit of PP2A (Ppp2ca) conditional knockout (CKO) in C57BL/6J mice. Here, we further explored the possible mechanisms by focusing on meiosis initiation and spermatogenesis. The deficiency of Ppp2ca in germ cells conspicuously disturbed spermatogonial differentiation and lead to pachytene arrest, accompanied by defects in programmed double-strand break (DSB) repair and meiotic sex chromosome inactivation (MSCI). Furthermore, Ppp2ca-deficient spermatocytes exhibited abnormal agglutination and cohesion complex degradation of chromosome, probably contributing to pachytene arrest. Our study demonstrates the irreplaceable role of PP2A in spermatogenesis and provide more evidences on azoospermia etiology.
2021-12-01 | GSE181132 | GEO
Project description:Protein phosphatase 2A propels follicular T helper cell development in lupus
| PRJNA858692 | ENA
Project description:Protein phosphatase 2A (PP2A) enzymes containing the regulatory subunit isoform B55α (PP2A-B55α) suppress HDAC5/MEF2 signalling in cardiac myocytes, implicating B55α in the transcriptional regulation of cardiac growth and fibrosis. The role of B55α in the heart has not been investigated. In this study, we generated and characterised two loss-of-function mouse models, with global or cardiomyocyte-specific disruption of the gene encoding B55α (Ppp2r2a). Mice with global homozygous knockout of B55α died in utero, but cardiac morphology was unremarkable compared with wildtype littermates. Mice with global heterozygous knockout of B55α had thinner left ventricular walls compared with wildtype mice at 12 months of age, an effect that was more pronounced in males. Mice with cardiomyocyte-specific deletion of B55α displayed normal cardiac morphology at 10-12 weeks of age, demonstrating that cardiomyocyte B55α is not required for postnatal heart growth. Despite no obvious morphological differences, gene expression analyses revealed extensive remodelling of the cardiac transcriptome in male, but not female, mice. In males, B55α knockout increased the expression of genes associated with extracellular matrix composition, and downregulated genes associated with mitochondrial energy production. This study reveals a sexually dimorphic role for B55α in postnatal cardiac transcriptional regulation and provides a foundation for future work investigating the role of B55α in cardiac stress settings.
2024-05-05 | GSE266131 | GEO
Project description:Pre-transplant sera from patients prior to heart transplant
2022-10-14 | PXD031426 | Pride
Project description:Segregation of homologous maternal and paternal centromeres to opposite poles during meiosis I depends on post-replicative crossing over between homologous non-sister chromatids, which creates chiasmata and therefore bivalent chromosomes. Destruction of sister chromatid cohesion along chromosome arms due to proteolytic cleavage of cohesin's Rec8 subunit by separase resolves chiasmata and thereby triggers the first meiotic division. This produces univalent chromosomes, the chromatids of which are held together by centromeric cohesin that has been protected from separase by shugoshin (Sgo1/MEI-S332) proteins. Here we show in both fission and budding yeast that Sgo1 recruits to centromeres a specific form of protein phosphatase 2A (PP2A). Its inactivation causes loss of centromeric cohesin at anaphase I and random segregation of sister centromeres at the second meiotic division. Artificial recruitment of PP2A to chromosome arms prevents Rec8 phosphorylation and hinders resolution of chiasmata. Our data are consistent with the notion that efficient cleavage of Rec8 requires phosphorylation of cohesin and that this is blocked by PP2A at meiosis I centromeres. Keywords: ChIP-chip, Mitosis, Meiosis, Cell cycle, Saccharomyces cerevisiae, Chromosome VI tiling array, Sgo1, Pp2A, Cse4, Ndc10, Rts1, Rec8
2006-05-10 | GSE4791 | GEO
Project description:Transcriptional regulation mediated by H2A.Z via ANP32e-dependent inhibition of protein phosphatase 2A
| PRJNA413542 | ENA