Project description:Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction, mostly because these remain unknown. Our prior work has focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations. In this study, we used a bulk (entire biopsy) tissue proteomics approach to evaluate mechanisms of tissue dysfunction in cardiac AL/ATTR. We included 76 ATTR cases and 27 AL cases. In stage 3 AL patients, pathways involved in coagulation, extracellular matrix (ECM) remodeling, epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia and clathrin-mediated endocytosis were increased compared to stage 1/2,whereas pathways involved in healthy cardiac metabolism and proteostasis were decreased. In Mayo stage 2/3 ATTR, immunoglobulin proteins, complement and keratin pathways were increased compared to stage 1. Principal component analyses identified an ATTR group with worse survival independent of existing staging systems that also showed upregulation of complement and downregulation of oxidative phosphorylation pathways. Finally, when comparing AL with ATTR, complement proteins were increased in ATTR whereas clathrin-mediated endocytosis , mRNA splicing, spliceosome pathways and ribosomal proteins were increased in AL. Clathrin-mediated endocytosis has been implicated in Aβ amyloid clearance by non-immune cells in the setting of Alzheimer’s disease and could represent a proteostatic mechanism of cardiomyocytes in response to AL fibrils. Impaired spliceosome and translation machinery has been associated with cardiac ECM-R in other cardiomyopathies. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis including activation of the complement cascade, especially among ATTR patients with worse outcomes.
Project description:This SuperSeries is composed of the following subset Series: GSE17823: Mouse cardiac tissue, polysomes and monosomes: Vehicle treated control vs. 15mg/kg doxorubicin GSE17826: Mouse cardiac tissue: Vehicle treated control vs. 15mg/kg doxorubicin GSE17830: Mouse cardiac tissue, polysomes and monosomes: Vehicle treated control vs. 25mg/kg DMNQ GSE17915: Mouse cardiac tissue: Vehicle treated control vs. 25mg/kg DMNQ Refer to individual Series
Project description:Background and Objective: Currently, the cells for transplantation were derived from either autologous or allogeneic tissue. The former has a drawback that the quality of donor cells could depend on the patient’s condition, and the quantity could also be limited. To solve these problems, we investigated the potential of allogeneic cardiac mesenchymal progenitors (CMPs) derived from postmortem heart, which might be an immunological privileged like bone marrow-derived mesenchymal progenitors. Materials and Methods: We examined whether viable CMPs could be isolated from murine postmortem cardiac tissue that was harvested 24 hours postmortem. After two to three weeks propagation with high dose of basic fibroblast growth factor, we performed the cellular characteristics analyses, which included proliferation and differentiation property flow cytometric analyses, and microarray analyses. Results: Postmortem CMPs had longer lag phase after seeding than CMPs from living tissues, but they demonstrated the similar characteristics in all above examinations. In addition, global gene expression analysis by microarray indicated the similar characteristics between the cell derived from postmortem and living tissue. Conclusion: These results indicate allogeneic postmortem CMPs could have promising potential for cell transplantation as clinical applications, because of circumventing the issue of brain death. The samples were collected fom living or postmortem cardiac tissue (24 hr at 4C). We generated cardiac mesenchymal progenitors (CMPs) from these cardiac tissue, and compared global gene expression by AgilentMouse GE 8x60k Microarray. Adult, or fetal mouse heart RNAs were used as positive control. Adult mouse total heart RNAs were purchased from Clontech. Fetal mouse heart was extracted from fetus which is embryonic day 16.5 C57BL/6 strain. Tg means Transgenic mouse (C57BL/6-Tg(Myh6-EGFP)MG2).
Project description:Transcriptional profiling of mouse cardiac tissue treated with 15mg/kg doxorubicin in 10 ml/kg saline over an acute time course (0.5-120 hours) compared to time matched control animals treated with 10ml/kg saline.
Project description:Transcriptional profiling of mouse cardiac tissue treated with 15mg/kg doxorubicin in 10 ml/kg saline over an acute time course (0.5-120 hours) compared to time matched control animals treated with 10ml/kg saline. Two colour microarrays with time matched controls against 15mg/kg doxorubicin cardiac tissue. Time points studied were 0.5, 1, 2, 12, 24 and 120 hours following dosing, biological replicates n=>3 independent animals at each time point, technical replicate n>1 with reverse labelling at each time point. One array printed onto two slides (A and B), one replicate per array.
Project description:Transcriptional profiling of mouse cardiac tissue treated with 25mg/kg DMNQ in 10 ml/kg arachis oil over an acute time course (5 minutes-120 hours) compared to time matached control animals treated with 10ml/kg arachis oil