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Heart Failure Reviews Sep 2023The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular... (Review)
Review
The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.
Topics: Humans; Cardiomyopathy, Hypertrophic; Hypertrophy, Left Ventricular; Cardiomyopathies; Phenotype; Fabry Disease; Inflammation
PubMed: 37115472
DOI: 10.1007/s10741-023-10307-4 -
APMIS : Acta Pathologica,... Dec 2023Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent... (Review)
Review
Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent infections. The clinical presentation is highly variable, with a spectrum ranging from recurrent bacterial and opportunistic infections to concomitant autoimmune diseases and, sometimes malignant pathologies. Due to heterogeneous clinical phenotypes and the lack of adequate diagnostic criteria, its recognition is often challenging, even delaying it by years. It is one of the most unusual, less studied form of the immune deficiency syndromes with a still unknown pathophysiology. It was initially considered a thymoma-associated variant of primary antibody deficiencies with a reduced or absent number of mature B cells, but it later emerged that significant defects of T cell-mediated immune functions are the underlying cause of opportunistic infections. On the basis of current evidence, Good's syndrome is evaluated as a distinct acquired form of combined immunodeficiency states and classified as a phenocopy of primary immunodeficiency diseases. Epigenetic and acquired genetic factors can play an ultimate role in its evolution.
Topics: Adult; Humans; Thymoma; Immunologic Deficiency Syndromes; Thymus Neoplasms; Primary Immunodeficiency Diseases; Opportunistic Infections
PubMed: 37729389
DOI: 10.1111/apm.13351 -
ELife Oct 2023The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key...
The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing and , two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.
Topics: Animals; Adult; Humans; MicroRNAs; Neurons; Hippocampus; Interneurons; Brain; Mammals
PubMed: 37862092
DOI: 10.7554/eLife.82729 -
Developmental Cell Oct 2023The microenvironment profoundly influences tumor initiation across numerous tissues but remains understudied in brain tumors. In the cerebellum, canonical Wnt signaling...
The microenvironment profoundly influences tumor initiation across numerous tissues but remains understudied in brain tumors. In the cerebellum, canonical Wnt signaling controlled by Norrin/Frizzled4 (Fzd4) activation in meningeal endothelial cells is a potent inhibitor of preneoplasia and tumor progression in mouse models of Sonic hedgehog medulloblastoma (Shh-MB). Single-cell transcriptome profiling and phenotyping of the meninges indicate that Norrin/Frizzled4 sustains the activation of meningeal macrophages (mMΦs), characterized by Lyve1 and CXCL4 expression, during the critical preneoplastic period. Depleting mMΦs during this period enhances preneoplasia and tumorigenesis, phenocopying the effects of Norrin loss. The anti-tumorigenic function of mMΦs is derived from the expression of CXCL4, which counters CXCL12/CXCR4 signaling in pre-tumor cells, thereby inhibiting cell-cycle progression and promoting migration away from the pre-tumor niche. These findings identify a pivotal role for mMΦs as key mediators in chemokine-regulated anti-cancer crosstalk between the stroma and pre-tumor cells in the control of MB initiation.
Topics: Mice; Animals; Medulloblastoma; Hedgehog Proteins; Endothelial Cells; Wnt Signaling Pathway; Cerebellar Neoplasms; Tumor Microenvironment
PubMed: 37774709
DOI: 10.1016/j.devcel.2023.08.033 -
Nature Communications Aug 2023In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage...
In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.
Topics: Animals; Mice; Chromatin; Chromosomes; DNA; Hematopoiesis; Mitosis; GATA2 Transcription Factor
PubMed: 37580379
DOI: 10.1038/s41467-023-40391-x -
American Journal of Transplantation :... Mar 2024In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce...
In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.
Topics: Animals; Mice; Cellular Senescence; Senotherapeutics; Mice, Inbred C57BL; Organ Transplantation; DNA; Aging
PubMed: 37913871
DOI: 10.1016/j.ajt.2023.10.013 -
Journal of Clinical Medicine Nov 2023Fabry disease (FD) is a genetic lysosomal storage disease with frequent cardiovascular involvement, whose presence is a major determinant of adverse clinical outcomes.... (Review)
Review
Fabry disease (FD) is a genetic lysosomal storage disease with frequent cardiovascular involvement, whose presence is a major determinant of adverse clinical outcomes. As a potentially treatable cause of left ventricular hypertrophy (LVH) and heart failure with preserved ejection fraction, the early recognition of FD is crucial to initiate enzyme replacement therapy and improve long-term prognosis. Multimodality imaging plays a central role in the evaluation of patients with FD and helps in the differential diagnosis of other conditions presenting with LVH. In the present review, we explore the current applications of multimodality cardiac imaging, in particular echocardiography and cardiovascular magnetic resonance, in the diagnosis, prognostic assessment, and follow-up of patients with FD.
PubMed: 38002674
DOI: 10.3390/jcm12227061 -
Circulation Research Jul 2023Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake...
BACKGROUND
Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis.
METHODS
We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell model of 2 inherited mutations ( []-R141W and []-L185F) that lead to dilated cardiomyopathy (DCM), a frequent cause of heart failure, to study the underlying molecular dysfunctions of DCM mutations.
RESULTS
We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell-derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the mutation in DCM patient-derived induced pluripotent stem cells, treatment with a peptide, Rho activator II, or iron supplementation rescued the molecular disease pathway and recovered contractility. Phenocopying the effects of the mutation into WT induced pluripotent stem cell-derived cardiomyocytes could be ameliorated by iron supplementation.
CONCLUSIONS
Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure.
Topics: Humans; Myocytes, Cardiac; Mutation; Cardiomyopathy, Dilated; Induced Pluripotent Stem Cells; Iron Deficiencies; Heart Failure; Iron; Clathrin
PubMed: 37313752
DOI: 10.1161/CIRCRESAHA.122.321157 -
Nature Communications May 2024In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and...
In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.
Topics: Animals; Humans; Male; Mice; Calcium; Calcium Channels; Diabetes Mellitus, Type 2; Diet, High-Fat; Galectin 3; Glucose; Insulin; Insulin Secretion; Insulin-Secreting Cells; Macrophages; Mice, Inbred C57BL; Mice, Knockout
PubMed: 38693121
DOI: 10.1038/s41467-024-47959-1 -
JCI Insight Dec 2023Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of...
Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR toward apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.
Topics: Animals; Humans; Mice; Cochlea; Deafness; Hair; Hair Cells, Auditory; Hearing Loss
PubMed: 37943620
DOI: 10.1172/jci.insight.172665