Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice

Bartoli, Fiona; Evans, Elizabeth L.; Blythe, Nicola M; Stewart, Leander; Chuntharpursat‐Bon, Eulashini; Debant, Marjolaine; Musialowski, Katie E; Lichtenstein, Laeticia; Parsonage, Gregory; Futers, T. Simon; Turner, Neil A.; Beech, David J.

doi:10.3390/cells11071199

Cited by 17 publications

(12 citation statements)

References 94 publications

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“…Piezo1 has been found to play a critical role in the outflow tract and aortic valve development [ 124 , 125 ]. Since its expression had been shown to be present in both cardiomyocytes and cardiac fibroblasts [ 96 , 126 , 127 ], possible correlations between this channel and diseases of the cardiovascular system are a natural next focus for investigation. Table 1 summarizes the current literature, reviewed below, about Piezo1 dysfunctional regulation in cardiac cells (myocytes and fibroblasts) and our preliminary hypothesis about its beneficial targeting in fibroblasts.…”

Section: Piezo1 and The Heartmentioning

confidence: 99%

“…Specifically, Piezo1 involvement in cardiac fibrosis was already taken into consideration by Fiona Bartoli et al in a very recent article [ 126 ]. Their work shows that a global gain-of-function Piezo1 mutation in mice is responsible for the amplificated calcium flow and both the overstimulated downstream p38 signaling and IL-6 secretion in cardiac fibroblasts.…”

Section: Piezo1 and The Heartmentioning

confidence: 99%

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Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

Braidotti

Chen

Long³

et al. 2022

IJMS

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Fibrotic tissues share many common features with neoplasms where there is an increased stiffness of the extracellular matrix (ECM). In this review, we present recent discoveries related to the role of the mechanosensitive ion channel Piezo1 in several diseases, especially in regulating tumor progression, and how this can be compared with cardiac mechanobiology. Based on recent findings, Piezo1 could be upregulated in cardiac fibroblasts as a consequence of the mechanical stress and pro-inflammatory stimuli that occurs after myocardial injury, and its increased activity could be responsible for a positive feedback loop that leads to fibrosis progression. The increased Piezo1-mediated calcium flow may play an important role in cytoskeleton reorganization since it induces actin stress fibers formation, a well-known characteristic of fibroblast transdifferentiation into the activated myofibroblast. Moreover, Piezo1 activity stimulates ECM and cytokines production, which in turn promotes the phenoconversion of adjacent fibroblasts into new myofibroblasts, enhancing the invasive character. Thus, by assuming the Piezo1 involvement in the activation of intrinsic fibroblasts, recruitment of new myofibroblasts, and uncontrolled excessive ECM production, a new approach to blocking the fibrotic progression can be predicted. Therefore, targeted therapies against Piezo1 could also be beneficial for cardiac fibrosis.

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Section: Piezo1 and The Heartmentioning

confidence: 99%

Section: Piezo1 and The Heartmentioning

confidence: 99%

Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

Braidotti

Chen

Long³

et al. 2022

IJMS

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“…This is certainly the case for the hereditary xerocytosis where gain of function variants in PIEZO1 affect red blood cell physiology. Although, no data is available at present regarding the prevalence of cardiac arrhythmias in patients suffering from this condition, mice have been engineered to contain a specific gain of function PIEZO1 mutation found in these patients [22]. Interestingly, these animals develop cardiac hypertrophy and fibrosis, a problem primarily associated with dysfunctional fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Piezo1 Activation Induces Cardiac Arrhythmia

Rolland¹,

Torrente²,

Bourinet³

et al. 2023

Preprint

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The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the center of this system is the heart which must detect these changes and adjust its performance accordingly. Mechano-electric feedback provides a rapid mechanism for detecting even subtle changes in the mechanical environment and transducing these signals into electrical responses which can adjust a variety of cardiac parameters such as heart rate and contractility. However, pathological conditions can disrupt this intricate mechanosensory system and manifest as potentially life-threatening cardiac arrhythmias. Mechanosensitive ion channels are thought to be the main proponents of mechano-electric feedback as they provide a rapid response to mechanical stimulation and can directly affect cardiac electrical activity. Here we demonstrate that the mechanosensitive ion channel Piezo1 is expressed in zebrafish cardiomyocytes. Furthermore, chemically prolonging Piezo1 activation in zebrafish results in cardiac arrhythmias indicating that this ion channel plays an important role in mechano-electric feedback. This also raises the possibility that Piezo1 gain of function mutations could be linked to heritable cardiac arrhythmias such as atrial fibrillation in humans.

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“…COL3A1 plays a pivotal role in the extracellular matrix. It has been reported that the abnormal expression of COL3A1 was closely associated with fibrosis in the cardiovascular system and spinal ligaments, indicating COL3A1’s capacity to maintain the functions of fibroblasts 39,40 . Rachel et al found that patients with vascular Ehlers‐Danlos syndrome, a genetic disease caused by the COL3A1 exon skipping mutations and presented with increased vascular fragility, suffered from systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

COL3A1: Potential prognostic predictor for head and neck cancer based on immune‐microenvironment alternative splicing

Shen

Wang

et al. 2022

Cancer Medicine

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We aimed to identify a novel prognostic biomarker for head and neck squamous cell carcinoma (HNSCC) based on tumor immunology‐related alternative splicing (AS). Data for 502 HNSCC and 44 normal samples were obtained from the TCGA database and used to establish an AS‐related risk model through univariate, least absolute shrinkage, and selection operator Cox regression analyses. Fresh HNSCC and normal oral tissues were surgically obtained from 44 HNSCC patients. Western blotting and quantitative reverse transcription‐PCR were used to assess gene expression levels. Kaplan–Meier was performed to evaluate patients' overall survival (OS) rate. The CIBERSORT algorithm, single‐sample gene set enrichment analysis, and immune checkpoint analyses were performed to compare immune activities between subgroups. The risk model was established using 10 pivotal AS events first. Collagen Type III Alpha 1 Chain (COL3A1) were screened based on |log2FC| ≥ 1 and FDR < 0.05 criteria. COL3A1 expression levels in HNSCC tissues were elevated relative to normal tissues (p < 0.001). Moreover, COL3A1 was a reliable biomarker for HNSCC patients' prognostic prediction in both cohorts (p < 0.001, p = 0.0085, respectively). COL3A1 protein (p = 0.0054) and mRNA (p < 0.0001) levels were correlated with HNSCC differentiation. Furthermore, the T stage was correlated with COL3A1 expression (p = 0.043), and COL3A1 expression was an independent prognostic predictor for HNSCC patients (p = 0.006). Compared with the risk model, COL3A1 was better at evaluating immune cell infiltrations, immune activities, and immune checkpoint gene expressions of HNSCC lesions.

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Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice

Cited by 17 publications

References 94 publications

Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

Prolonged Piezo1 Activation Induces Cardiac Arrhythmia

COL3A1: Potential prognostic predictor for head and neck cancer based on immune‐microenvironment alternative splicing

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