Dataset Information

Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.

ABSTRACT: Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are among the leading causes of morbidity and mortality worldwide. Such genetically driven forms of hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathies are chronic, debilitating diseases that result from biomechanical defects in cardiac muscle contraction and frequently progress to heart failure (HF). Locus and allelic heterogeneity, as well as clinical variability combined with genetic and phenotypic overlap between different cardiomyopathies, have challenged proper clinical prognosis and provided an incentive for identification of pathogenic variants. This review attempts to provide an overview of inherited cardiomyopathies with a focus on their genetic etiology in myosin regulatory (RLC) and essential (ELC) light chains, which are EF-hand protein family members with important structural and regulatory roles. From the clinical discovery of cardiomyopathy-linked light chain mutations in patients to an array of exploratory studies in animals, and reconstituted and recombinant systems, we have summarized the current state of knowledge on light chain mutations and how they induce physiological disease states via biochemical and biomechanical alterations at the molecular, tissue, and organ levels. Cardiac myosin RLC phosphorylation and the N-terminus ELC have been discussed as two important emerging modalities with important implications in the regulation of myosin motor function, and thus cardiac performance. A comprehensive understanding of such triggers is absolutely necessary for the development of target-specific rescue strategies to ameliorate or reverse the effects of myosin light chain-related inherited cardiomyopathies.

SUBMITTER: Yadav S

PROVIDER: S-EPMC6476665 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.

Yadav Sunil S Sitbon Yoel H YH Kazmierczak Katarzyna K Szczesna-Cordary Danuta D

Pflugers Archiv : European journal of physiology 20190131 5

Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are among the leading causes of morbidity and mortality worldwide. Such genetically driven forms of hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathies are chronic, debilitating diseases that result from biomechanical defects in cardiac muscle contraction and frequently progress to heart failure (HF). Locus and allelic heterogeneity, as well as clinical variability co ...[more]

PMID: 30706179

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Project description:MicroRNAs (miRNAs) are non-coding RNAs that function as regulators of gene expression and thereby contribute to the complex disease phenotypes. Hypertrophic cardiomyopathy (HCM) and Dilated cardiomyopathy (DCM) can cause sudden cardiac death and eventually develop into heart failure. However, they have different clinical and pathophysiological phenotype and the expressional spectrum of miRNAs in left ventricles of HCM and DCM has never been compared before.This study selected 30 human left ventricular heart samples belonged to three diagnostic groups (Control, HCM, DCM). Each group has ten samples. Based on previous findings, the expression of 13 different microRNAs involving heart failure and hypertrophy (miR-1-3p, miR-10b, miR-21, miR-23a, miR-27a, miR-29a, miR-133a-3p, miR-142-3p, miR-155, miR-199a-3p, miR-199a-5p, miR-214, miR-497) was measured. 17 HCM patients were included as second group to validate the associations.We found miR-155, miR-10b and miR-23a were highly expressed in both HCM and DCM compared with control. MiR-214 was downregulated and miR-21 was upregulated in DCM but not in HCM. We also identified miR-1-3p and miR-27a expressed significantly different between HCM and DCM and both miRNAs downregulated in HCM. And only miR-1-3p correlated with left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) that reflected the cardiac function in HCM. A second HCM group also confirmed this correlation. We then predicted Chloride voltage-gated channel 3 (Clcn3) as a direct target gene of miR-1-3p using bioinformatics tools and confirmed it by Luciferase reporter assay.Our data demonstrated that different cardiomyopathies had unique miRNA expression pattern. And the expression levels of miR-1-3p and miR-27a had disease-specificity and sensitivity in HCM, whereas only miR-1-3p was significantly associated with left ventricular function in HCM identifying it as a potential target to improve the cardiac function in end-stage HCM. We also provide Clcn3 as a direct target of miR-1-3p which sheds light on the mechanism of HCM.

Project description:Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.

Dataset Information

Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.

Publications

Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.

Similar Datasets

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