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Circulation research [journal]
- A Detailed Analysis of Bone Marrow from Patients with Ischemic Heart Disease and Left Ventricular Dysfunction: BM CD34, CD11b and Clonogenic Capacity as Biomarkers for Clinical Outcomes. [JOURNAL ARTICLE]
- Circ Res 2014 Aug 18.
Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche following acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular dysfunction (LVD). Methods and Results: BM from 280 patients with IHD and LVD were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% vs. 2.3-2.7% in other cohorts; p < 0.05). BM-derived endothelial colonies were significantly decreased (p < 0.05). Increased BM CD11b(+) cells associated with worse left ventricular ejection fraction (LVEF) after AMI (p < 0.05). While increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% vs. +2.3%, p=0.03, for AMI patients; and +6.6% vs. -0.02%, p=0.021 for chronic IHD patients), decreased BM CD34(+) percentage in chronic IHD patients correlated with decrement in LVEF after cell therapy (-2.9% vs. +0.7%, p=0.0355). Conclusions: In this study we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34(+) cell nadir seven days after AMI, a negative correlation between CD11b percentage and post-infarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and/or reversal of co-morbid BM impairment.
- Correction. [Journal Article]
- Circ Res 2014 Aug 15; 115(5):e10.
- Deepak srivastava: follows his heart to study the heart. [Journal Article]
- Circ Res 2014 Aug 15; 115(5):481-3.
- Study of exonic variation identifies incremental information regarding lipid-related and coronary heart disease genes. [Journal Article]
- Circ Res 2014 Aug 15; 115(5):478-80.
- Ceramide signaling in the coronary microcirculation: a double-edged sword? [Editorial]
- Circ Res 2014 Aug 15; 115(5):475-7.
- Peeking Into a Cool Future: Genome Editing to Delete PCSK9 and Control Hypercholesterolemia in a Single Shot. [Editorial]
- Circ Res 2014 Aug 15; 115(5):472-4.
- Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction. [JOURNAL ARTICLE]
- Circ Res 2014 Aug 11.
Rationale: The Notch pathway plays a key role in stimulating mammalian cardiomyocyte proliferation during development and in the early postnatal life; in adult zebrafish, reactivation of this pathway is also essential to drive cardiac regeneration after injury. Objective: We wanted to assess efficacy of Notch pathway stimulation in neonatal and adult hearts as a means to induce cardiac regeneration after myocardial infarction in mice. Methods and Results: In early postnatal life, cardiomyocyte exit from the cell cycle was paralleled by decreased Notch signaling and the establishment of a repressive chromatin environment at Notch responsive genes, characterized by recruitment of the Polycomb Group Ezh2 methyltransferase and the acquisition of the H3K27me3 histone mark, as detected by chromatin immunoprecipitation. Forced Notch pathway activation by AAV gene transfer of activated Notch1 or its ligand Jagged 1 expanded the proliferative capacity of neonatal cardiomyocytes; this correlated with increased transcription of Notch target genes and maintenance of an open chromatin conformation at their promoters. The same AAV vectors, however, were largely ineffective in stimulating cardiac repair after myocardial infarction in adult mice, despite optimal and long lasting transgene expression. Analysis of Notch-responsive promoters in adult cardiomyocytes showed marks of repressed chromatin and irreversible CpG DNA methylation. Induction of adult cardiomyocyte re-entry into the cell cycle with microRNAs was independent from Notch pathway reactivation. Conclusions: Notch pathway activation is crucial in regulating cardiomyocyte proliferation during the early postnatal life, but is largely ineffective in driving cardiac regeneration in adults, due to permanent epigenetic modification at Notch responsive promoters.
- Adipose Stromal Cells Differentiate Along a Smooth Muscle Lineage Pathway upon Endothelial Cell Contact via Induction of Activin A. [JOURNAL ARTICLE]
- Circ Res 2014 Aug 11.
Rationale: Adipose stromal cells (ASC) are therapeutically potent progenitor cells that possess properties of pericytes. In vivo, ASC in combination with endothelial cells (EC) establish functional multilayer vessels, in which ASC form the outer vessel layer and differentiate into mural cells. Objective: To identify factors responsible for ASC differentiation towards the smooth muscle cell (SMC) phenotype via interaction with EC. Methods and Results: An in vitro model of EC co-cultivation with ASC was employed, in which EC organized into vascular cords, accompanied by ASC migration towards EC and up-regulation of αSMA, SM22α, and calponin expression. Conditioned media (CM) from EC-ASC, but not from EC cultures, induced SMC protein expression in ASC monocultures. EC-ASC co-cultivation induced marked accumulation of activin A, but not TGFβ1 in CM. This was attributed to induction of activin A expression in ASC upon contact with EC. While TGFβ and activin A were individually sufficient to initiate expression of SMC antigens in ASC, only activin A IgG blocked the effect of EC-ASC CM. While TGFβ was able to induce activin A expression in ASC, in co-cultures this induction was TGFβ-independent. In EC-ASC co-cultures activin A IgG or ALK4/5/7 receptor inhibitors blocked expression of αSMA in ASC in the absence of direct EC-cord contact, but this inhibition was circumvented in ASC by direct EC contact. Conclusions: EC initiate a SMC differentiation program in adjacent ASC, and propagate this differentiation in distant ASC, by induction of activin A expression.
- Sumo E2 Ligase UBC9 is Required for Efficient Protein Quality Control in Cardiomyocytes. [JOURNAL ARTICLE]
- Circ Res 2014 Aug 5.
Rationale: Impairment of proteasomal function is pathogenic in a number of cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation and, while the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control (PQC) is not fully understood. Objective: To determine the role of UBC9, a SUMO-conjugating enzyme, in cardiomyocyte PQC. Methods and Results: Gain- and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes while knockdown of UBC9 by siRNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein, GFPu. Subsequently, UBC9's effects on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte specific expression of a mutated alpha B crystallin, CryAB(R120G). CryAB(R120G) expression leads to aggregate formation and decreased proteasomal function. Co-infection of UBC9-adenovirus with CryAB(R120)G virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels. Conclusions: UBC9 plays a significant role in cardiomyocyte PQC and its activity can be exploited to reduce toxic levels of misfolded or aggregated proteins in cardiomyopathy.
- FOXF1 Transcription Factor Is Required for Formation of Embryonic Vasculature by Regulating VEGF Signaling in Endothelial Cells. [JOURNAL ARTICLE]
- Circ Res 2014 Aug 4.
Rationale: Inactivating mutations in the FOXF1 gene locus are frequently found in patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV), a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardio-vascular and gastro-intestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal and gall bladder morphogenesis. Objective: While FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and ACD/MPV patients remain uncharacterized due to lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. Methods and Results: A novel mouse line harboring Foxf1-floxed alleles was generated by homologous recombination. Tie2-Cre and Pdgfb-CreER transgenes were used to delete Foxf1 from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia and vascular abnormalities in the lung, placenta, yolk sac and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited VEGF signaling and decreased expression of endothelial genes critical for vascular development, including VEGF receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2 and the non-coding RNA Fendrr. ChIP assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1 and Tie2 genes are direct transcriptional targets of FOXF1. Conclusions: FOXF1 is required for formation of embryonic vasculature by regulating endothelial genes critical for vascular development and VEGF signaling.