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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-proteasome system (UPS) plays a central role in maintaining protein homeostasis, emphasized by a myriad of diseases that are associated with altered UPS function such as cancer, muscle-wasting, and neurodegeneration. Protein ubiquitination plays a central role in both the promotion of proteasomal degradation as well as cellular signaling through regulation of the stability of transcription factors and other signaling molecules. Substrate-specificity is a critical regulatory step of ubiquitination and is mediated by ubiquitin ligases. Recent studies implicate ubiquitin ligases in multiple models of cardiac diseases such as cardiac hypertrophy, atrophy, and ischemia/reperfusion injury, both in a cardioprotective and maladaptive role. Therefore, identifying physiological substrates of cardiac ubiquitin ligases provides both mechanistic insights into heart disease as well as possible therapeutic targets. Current methods identifying substrates for ubiquitin ligases rely heavily upon non-physiologic in vitro methods, impeding the unbiased discovery of physiological substrates in relevant model systems. Here we describe a novel method for identifying ubiquitin ligase substrates utilizing tandem ubiquitin binding entities technology, two-dimensional differential in gel electrophoresis, and mass spectrometry, validated by the identification of both known and novel physiological substrates of the ubiquitin ligase MuRF1 in primary cardiomyocytes. This method can be applied to any ubiquitin ligase, both in normal and disease model systems, in order to identify relevant physiological substrates under various biological conditions, opening the door to a clearer mechanistic understanding of ubiquitin ligase function and broadening their potential as therapeutic targets.
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PMID:Diggin' on u(biquitin): a novel method for the identification of physiological E3 ubiquitin ligase substrates. 2369 82

In the cell, the proteasome and lysosomes represent the most important proteolytic machineries, responsible for the protein degradation in the ubiquitin-proteasome system (UPS) and autophagy, respectively. Both the UPS and autophagy are essential to protein quality and quantity control. Alterations in cardiac proteasomal and lysosomal degradation are remarkably associated with most heart disease in humans and are implicated in the pathogenesis of congestive heart failure. Studies carried out in animal models and in cell culture have begun to establish both sufficiency and, in some cases, the necessity of proteasomal functional insufficiency or lysosomal insufficiency as a major pathogenic factor in the heart. This review article highlights some recent advances in the research into proteasome and lysosome protein degradation in relation to cardiac pathology and examines the emerging evidence for enhancing degradative capacities of the proteasome and/or lysosome as a new therapeutic strategy for heart disease. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".
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PMID:Proteasomal and lysosomal protein degradation and heart disease. 2423 9

Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism-epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.
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PMID:Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype. 2479 59

Proteotoxicity refers to the detrimental effects of damaged/misfolded proteins on the cell. Cardiac muscle is particularly susceptible to proteotoxicity because sustained and severe proteotoxic stress leads to cell death and the cardiac muscle has very limited self-renewal capacity. The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are two major pathways responsible for degradation of most cellular proteins. Alterations of UPS and ALP functions are associated with the accumulation of proteotoxic species in the heart, a key pathological feature of common forms of heart disease including idiopathic, ischemic, and pressure-overloaded cardiomyopathies and a large subset of congestive heart failure. Emerging evidence suggests that proteasome inhibition or impairment activates autophagy and conversely, acute ALP inhibition may sometimes increase intrinsic proteasome peptidase activities but chronic ALP inhibition hinders UPS performance in ubiquitinated protein degradation. The exact molecular basis on which the two degradative pathways interact remains largely undefined. Here we review current understanding of the roles of the UPS and autophagy in the control of cardiac proteotoxicity, with a specific focus on the crosstalk between the two pathways. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
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PMID:The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity. 2509 68

AL amyloidosis belongs to the group of conformational diseases. It is the most common type of amyloidosis with an estimated 500 new cases per year in France. It is due to a small and usually indolent plasma cell clone which synthesizes an unstable, misfolded monoclonal immunoglobulin light chain that is prone to aggregate and form amyloid fibrils. Non-invasive biopsy such as abdominal fat aspiration or minor salivary gland biopsy should be performed to confirm the diagnosis and if negative, involved tissues have to be examined. Clinical presentation is very diverse, as AL amyloidosis can affect almost any organ or tissue in the body, other than the brain. The kidney is the most frequent organ involved, whereas heart disease characterized by restrictive cardiomyopathy is the most severe. Early diagnosis, before advanced cardiomyopathy, is essential for improving outcome. The association of alkylating agent and high-dose dexamethasone is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylating agents achieve high response rates. Close monitoring of clonal and organ response is mandatory to guide therapy changes and duration. New treatments designed to eliminate amyloid deposits are under development.
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PMID:[AL amyloidosis]. 2519 19

Heart disease has become the number one killer of human health, and its diagnosis depends on many features, such as age, blood pressure, heart rate and other dozens of physiological indicators. Although there are so many risk factors, doctors usually diagnose the disease depending on their intuition and experience, which requires a lot of knowledge and experience for correct determination. To find the hidden medical information in the existing clinical data is a noticeable and powerful approach in the study of heart disease diagnosis. In this paper, sparse logistic regression method is introduced to detect the key risk factors using L(1/2) regularization on the real heart disease data. Experimental results show that the sparse logistic L(1/2) regularization method achieves fewer but informative key features than Lasso, SCAD, MCP and Elastic net regularization approaches. Simultaneously, the proposed method can cut down the computational complexity, save cost and time to undergo medical tests and checkups, reduce the number of attributes needed to be taken from patients.
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PMID:Application of L1/2 regularization logistic method in heart disease diagnosis. 2522 56

The prevalence of heart disease, especially heart failure, continues to increase, and cardiovascular disease remains the leading cause of death worldwide. As cardiomyocytes are essentially irreplaceable, protein quality control is pivotal to cellular homeostasis and, ultimately, cardiac performance. Three evolutionarily conserved mechanisms-autophagy, the unfolded protein response, and the ubiquitin-proteasome system-act in concert to degrade misfolded proteins and eliminate defective organelles. Recent advances have revealed that these mechanisms are intimately associated with cellular metabolism. Going forward, comprehensive understanding of the role of protein quality control mechanisms in cardiac pathology will require integration of metabolic pathways and metabolic control.
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PMID:Protein quality control and metabolism: bidirectional control in the heart. 2565 Nov 76

Alteration of ubiquitin-proteasome system (UPS) mediated protein degradation has been implicated in the progression from a large subset of heart disease to congestive heart failure, rendering it extremely important to elucidate the cellular and molecular mechanism by which the UPS is regulated. Cullin-RING ligases (CRLs) represent the largest family of ubiquitin ligases crucial for UPS-dependent proteolysis. Serving as a cullin deneddylase, the COP9 signalosome (CSN) regulates the activity and assembly of CRLs. In the past several years, emerging studies have begun to unveil the role of the CSN and some of the CRLs in cardiomyocytes or the heart under physiological and pathological conditions. This review article will highlight and analyze these recent progresses and provide the author's perspective on the future directions for this research field.
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PMID:The COP9 signalosome and cullin-RING ligases in the heart. 2606 89

White matter disruptions have been identified in individuals with congenital heart disease (CHD). However, no specific theory-driven relationships between microstructural white matter disruptions and cognition have been established in CHD. We conducted a two-part study. First, we identified significant differences in fractional anisotropy (FA) of emerging adults with CHD using Tract-Based Spatial Statistics (TBSS). TBSS analyses between 22 participants with CHD and 18 demographically similar controls identified five regions of normal appearing white matter with significantly lower FA in CHD, and two higher. Next, two regions of lower FA in CHD were selected to examine theory-driven differential relationships with cognition: voxels along the left uncinate fasciculus (UF; a tract theorized to contribute to verbal memory) and voxels along the right middle cerebellar peduncle (MCP; a tract previously linked to attention). In CHD, a significant positive correlation between UF FA and memory was found, r(20)=.42, p=.049 (uncorrected). There was no correlation between UF and auditory attention span. A positive correlation between MCP FA and auditory attention span was found, r(20)=.47, p=.027 (uncorrected). There was no correlation between MCP and memory. In controls, no significant relationships were identified. These results are consistent with previous literature demonstrating lower FA in younger CHD samples, and provide novel evidence for disrupted white matter integrity in emerging adults with CHD. Furthermore, a correlational double dissociation established distinct white matter circuitry (UF and MCP) and differential cognitive correlates (memory and attention span, respectively) in young adults with CHD.
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PMID:White Matter Integrity Dissociates Verbal Memory and Auditory Attention Span in Emerging Adults with Congenital Heart Disease. 2630 56

Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.
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PMID:Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features. 3218 68


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