4 results on '"Cannon EN"'
Search Results
2. NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy.
- Author
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Chelko SP, Penna VR, Engel M, Shiel EA, Centner AM, Farra W, Cannon EN, Landim-Vieira M, Schaible N, Lavine K, and Saffitz JE
- Subjects
- Animals, Mice, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Myocytes, Cardiac immunology, Humans, Arrhythmogenic Right Ventricular Dysplasia genetics, Arrhythmogenic Right Ventricular Dysplasia metabolism, Arrhythmogenic Right Ventricular Dysplasia pathology, Myocardium pathology, Myocardium metabolism, Myocardium immunology, Macrophages metabolism, Macrophages pathology, Macrophages immunology, Receptors, CCR2 genetics, Receptors, CCR2 metabolism, Signal Transduction, Disease Models, Animal, Desmoglein 2 genetics, Desmoglein 2 metabolism, NF-kappa B metabolism, NF-kappa B genetics
- Abstract
Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.
- Published
- 2024
- Full Text
- View/download PDF
3. Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model.
- Author
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McCarthy DM, Bell GA, Cannon EN, Mueller KA, Huizenga MN, Sadri-Vakili G, Fadool DA, and Bhide PG
- Subjects
- Animals, Conditioning, Classical drug effects, Disease Models, Animal, Female, Mice, Pregnancy, Protein-Tyrosine Kinases metabolism, Receptor, trkB metabolism, Brain-Derived Neurotrophic Factor metabolism, Cocaine pharmacology, Frontal Lobe drug effects, Memory drug effects, Prenatal Exposure Delayed Effects physiopathology, Reversal Learning drug effects, Signal Transduction drug effects
- Abstract
Prenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF) is a key regulator of cognitive functions, and because prenatal cocaine exposure increases the expression of BDNF and the phosphorylated form of its receptor, tyrosine kinase B (TrkB), we examined whether BDNF-TrkB signaling is involved in mediating the reversal learning deficit in prenatally cocaine-exposed mice. Systemic administration of a selective TrkB receptor antagonist restored normal reversal learning in prenatally cocaine-exposed mice, suggesting that increased BDNF-TrkB signaling may be an underlying mechanism of reversal learning deficits. Our findings provide novel mechanistic insights into the reversal learning phenomenon and may have significant translational implications because impaired cognitive flexibility is a key symptom in psychiatric conditions of developmental onset., (© 2016 S. Karger AG, Basel.)
- Published
- 2016
- Full Text
- View/download PDF
4. Prenatal Cocaine Exposure Alters BDNF-TrkB Signaling in the Embryonic and Adult Brain.
- Author
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McCarthy DM, Mueller KA, Cannon EN, Huizenga MN, Darnell SB, Bhide PG, and Sadri-Vakili G
- Subjects
- Aging, Animals, Brain growth & development, Female, Mice, Pregnancy, Prosencephalon metabolism, Protein-Tyrosine Kinases metabolism, RNA, Messenger metabolism, Receptor, trkB genetics, Brain drug effects, Brain-Derived Neurotrophic Factor metabolism, Cocaine pharmacology, Prenatal Exposure Delayed Effects metabolism, Receptor, trkB metabolism, Signal Transduction drug effects
- Abstract
Prenatal cocaine exposure remains a major public health concern because of its adverse effects on cognitive function. Although the molecular mechanisms underlying the cognitive impairment are not fully understood, brain-derived neurotrophic factor (BDNF) signaling via its receptor tyrosine kinase B (TrkB) is emerging as a potential candidate. We used a mouse model to examine the impact of ongoing cocaine exposure on BDNF expression in the dorsal forebrain on embryonic day 15 (E15) as well as the long-term effects of prenatal cocaine exposure on BDNF-TrkB signaling in the frontal cortex in early postnatal (postnatal day 16; P16) and adult (P60) male and female mice. We found that ongoing cocaine exposure decreased BDNF expression in the E15 dorsal forebrain, prenatal cocaine exposure did not alter BDNF or TrkB (total or phosphorylated) expression in the frontal cortex at P16, and that the prenatal cocaine exposure produced significant increases in BDNF, the activated (phosphorylated) form of TrkB, as well as Bdnf mRNA in the frontal cortex at P60. The increase in BDNF protein and mRNA expression at P60 was concurrent with hyperacetylation of histone H3 at the Bdnf promoter in the frontal cortex. The increase in frontal cortical BDNF and activated TrkB at P60 occurred in male but not female mice. Thus, our data demonstrate that ongoing cocaine exposure produces a decrease in BDNF expression in the embryonic brain, and that prenatal cocaine exposure produces a sex-specific increase in frontal cortical BDNF-TrkB signaling at P60 only in male mice. Lastly, hyperacetylation of histone H3 at the Bdnf promoter is one epigenetic mechanism mediating the effects of prenatal cocaine exposure on Bdnf expression at P60 in male mice., (© 2017 S. Karger AG, Basel.)
- Published
- 2016
- Full Text
- View/download PDF
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