Molecular mechanisms in the pathogenesis of arrhythmogenic cardiomyopathy

Saffitz, Jeffrey E.

doi:10.1016/j.carpath.2017.02.005

Cited by 4 publications

(3 citation statements)

References 29 publications

(80 reference statements)

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“…NF k B activation has been previously linked to the development of renal diseases [ 72 ]. Wang et al [ 73 ] found that nephropathy is mediated via activation of the tumor necrosis factor/NF k B pathway As NF k B regulates inflammatory factor transcription in mesangial and tubular epithelial cells, it plays a vital role in the development and progression of renal diseases [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

The Potential Protective Effect and Underlying Mechanisms of Physiological Unconjugated Hyperbilirubinemia Mediated by UGT1A1 Antisense Oligonucleotide Therapy in a Mouse Model of Cyclosporine A-Induced Chronic Kidney Disease

et al. 2022

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Cyclosporine A (CSA) is an immunosuppressive drug that has improved transplant survival rates. However, its use is often limited because it is thought to be linked to the development of chronic kidney disease after kidney transplants. This study aimed to investigate the protective effects and underlying mechanisms of physiological unconjugated (UC) hyperbilirubinemia mediated by UGT1A1 antisense oligonucleotide in a mouse model of CsA-induced chronic kidney disease, and match these with that of chitosan (CH) as a natural chelator against kidney injury. In the current study, CsA-treated mice were given an intravenous injection of UGT1A1 antisense morpholino oligonucleotide (16 µg/kg) every third day for 14 days. In serum samples, bilirubin, creatinine, and urea were determined. Markers of oxidative stress, antioxidant activities, and mRNA expression of target genes PPAR-α, cFn, eNOS, NF-B, AT1-R, ETA-R, Kim-1, and NGAL were measured in the kidney tissues. Moreover, histopathological examinations were carried out on the kidney tissue. Physiological UC hyperbilirubinemia could be a promising protective strategy against CsA-induced kidney disease in transplant recipients. UGT1A1 antisense oligonucleotide-induced physiological UC hyperbilirubinemia serum significantly protected against CsA-induced kidney dysfunction. UCB acts as a signaling molecule that protects against kidney disease through different mechanisms, including antioxidant, anti-inflammatory, and hormonal action, by activating nuclear hormone receptors (PPAR-α). Moreover, it significantly downregulated mRNA expression of NF-kB, ETA-R, iNOS, AT1-R, cFn, Kim-1, and NGAL in the kidney tissue and alleviated CsA-induced kidney histological changes in CsA-treated mice.

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Section: Discussionmentioning

confidence: 99%

The Potential Protective Effect and Underlying Mechanisms of Physiological Unconjugated Hyperbilirubinemia Mediated by UGT1A1 Antisense Oligonucleotide Therapy in a Mouse Model of Cyclosporine A-Induced Chronic Kidney Disease

et al. 2022

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“…This disease, which can predominantly affect the right ventricle (arrhythmogenic right ventricular cardiomyopathy or ARVC), the left ventricle (arrhythmogenic left ventricular cardiomyopathy (ALVC), or arrhythmogenic dilated cardiomyopathy (DCM)), or both (biventricular ACM) is generated by a large spectrum of genes including the lamin A/C gene (LMNA) [1]. Many ACM genes, such as LMNA [3], induce important alterations of the signal transduction and the intercellular communication mechanism in cardiac cells [4][5][6]. In 2015, Lanzicher et al investigated the biomechanical impact of LMNA missense mutations in neonatal rat ventricular myocytes (NRVM), and found damages on the actin cytoskeleton, suggesting loss of actin filament anchorage by dysfunction of the Int.…”

Section: Introductionmentioning

confidence: 99%

“…Sci. 2021, 22, x FOR PEER REVIEW 2 of 23 tion mechanism in cardiac cells [4][5][6]. In 2015, Lanzicher et al investigated the biomechanical impact of LMNA missense mutations in neonatal rat ventricular myocytes (NRVM), and found damages on the actin cytoskeleton, suggesting loss of actin filament anchorage by dysfunction of the laminar proteins at the nuclear membrane as the initiating alteration [7,8].…”

Section: Introductionmentioning

confidence: 99%

Compromised Biomechanical Properties, Cell–Cell Adhesion and Nanotubes Communication in Cardiac Fibroblasts Carrying the Lamin A/C D192G Mutation

Lachaize

Peña

Ciubotaru

et al. 2021

IJMS

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Clinical effects induced by arrhythmogenic cardiomyopathy (ACM) originate from a large spectrum of genetic variations, including the missense mutation of the lamin A/C gene (LMNA), LMNA D192G. The aim of our study was to investigate the biophysical and biomechanical impact of the LMNA D192G mutation on neonatal rat ventricular fibroblasts (NRVF). The main findings in mutated NRVFs were: (i) cytoskeleton disorganization (actin and intermediate filaments); (ii) decreased elasticity of NRVFs; (iii) altered cell–cell adhesion properties, that highlighted a strong effect on cellular communication, in particular on tunneling nanotubes (TNTs). In mutant-expressing fibroblasts, these nanotubes were weakened with altered mechanical properties as shown by atomic force microscopy (AFM) and optical tweezers. These outcomes complement prior investigations on LMNA mutant cardiomyocytes and suggest that the LMNA D192G mutation impacts the biomechanical properties of both cardiomyocytes and cardiac fibroblasts. These observations could explain how this mutation influences cardiac biomechanical pathology and the severity of ACM in LMNA-cardiomyopathy.

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Hippo cell signaling and HS-proteoglycans regulate tissue form and function, age-dependent maturation, extracellular matrix remodeling, and repair

Melrose

2024

American Journal of Physiology-Cell Physiology

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This review examined how Hippo cell signaling and HS-proteoglycans (HSPGs) regulate tissue form and function. Despite being a non-weight bearing tissue the brain is regulated by Hippo mechanoresponsive cell signalling pathways during embryonic development. HS-proteoglycans interact with growth factors, morphogens and extracellular matrix components to regulate development and pathology. Pikachurin and Eyes Shut interact with dystroglycan to stabilize the photoreceptor axoneme primary cilium and ribbon synapse facilitating phototransduction and neurotransduction with bipolar retinal neuronal networks in ocular vision, the primary human sense. Another HSPG, Neurexin interacts with structural and adaptor proteins to stabilize synapses and ensure specificity of neural interactions, and aids in synaptic potentiation and plasticity in neurotransduction. HSPGs also stabilize the blood brain barrier and motor neuron basal structures in the neuromuscular junction. Agrin and perlecan localize acetylcholinesterase and its receptors in the neuromuscular junction essential for neuromuscular control. The primary cilium is a mechanosensory hub on neurons, utilized by YAP-TAZ Hippo, Hh, Wnt, TGF-b/BMP receptor tyrosine kinase cell signaling. Members of the glypican HSPG proteoglycan family interact with Smoothened and Patched G-protein coupled receptors on the cilium to regulate Hh and Wnt signaling during neuronal development. Control of glycosyl sulfotransferases and endogenous protease expression by Hippo TAZ YAP represents a mechanism whereby the fine structure of HS-proteoglycans can be potentially modulated spatio-temporally to regulate tissue morphogenesis in a similar manner to how Hippo signaling controls sialyltransferase expression and mediation of cell-cell recognition, dysfunctional sialic acid expression is a feature of many tumors.

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Molecular mechanisms in the pathogenesis of arrhythmogenic cardiomyopathy

Cited by 4 publications

References 29 publications

The Potential Protective Effect and Underlying Mechanisms of Physiological Unconjugated Hyperbilirubinemia Mediated by UGT1A1 Antisense Oligonucleotide Therapy in a Mouse Model of Cyclosporine A-Induced Chronic Kidney Disease

The Potential Protective Effect and Underlying Mechanisms of Physiological Unconjugated Hyperbilirubinemia Mediated by UGT1A1 Antisense Oligonucleotide Therapy in a Mouse Model of Cyclosporine A-Induced Chronic Kidney Disease

Compromised Biomechanical Properties, Cell–Cell Adhesion and Nanotubes Communication in Cardiac Fibroblasts Carrying the Lamin A/C D192G Mutation

Hippo cell signaling and HS-proteoglycans regulate tissue form and function, age-dependent maturation, extracellular matrix remodeling, and repair

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