The mechanical regulation of RNA binding protein hnRNPC in the failing heart

Martino, Fabiana De; Varadarajan, Nandan Mysore; Perestrelo, Ana Rubina; Hejret, Václav; Durikova, Helena; Vukić, Dragana; Horváth, Vladimír; Cavalieri, Francesca; Caruso, Frank; Albihlal, Waleed S.; Gerber, André P.; O’Connell, Mary A.; Vaňáčová, Štěpánka; Pagliari, Stefania; Forte, Giancarlo

doi:10.1126/scitranslmed.abo5715

Cited by 11 publications

(11 citation statements)

References 110 publications

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“…During heart failure, HNRNPC physically interacts with myocardial ganglion proteins FHL2, PDLIM5, and MYH7 in the heart. Additionally, changes in the nuclear localization of HNRNPC are observed in response to changes in cellular stretch and skeleton tension [29]. These findings suggest the potential for reciprocal regulation between HNRNPC and the cytoskeleton.…”

Section: Lcp1 Is the Potential Target Of Hnrnpcmentioning

confidence: 81%

m6A Reader HNRNPC Facilitates Adipogenesis by Regulating Cytoskeletal Remodeling through Enhanced Lcp1 mRNA Stability

2024

Aging dis

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Reduced adipogenesis is a prominent characteristic of aging adipose tissue and is closely tied to the development of metabolic disorders associated with aging. Epigenetic modification plays a crucial role in the aging process, yet the role of N 6 -methyladenosine (m 6 A), the most prevalent RNA modification, in regulating adipose tissue aging remains uncertain. Our study found that levels of m 6 A and its recognition protein, heterogeneous nuclear ribonucleoprotein C (HNRNPC), decrease in adipose tissue as individuals age. Lower levels of HNRNPC were also linked to reduced adipogenesis during aging. Through loss and gain of function experiments with HNRNPC, we established a positive correlation between HNRNPC and adipogenesis in vitro. Hnrnpc-APKO mice displayed decreased adipogenesis, increased insulin resistance, elevated expression of aging-related and inflammation-related genes, decreased lipogenesis-related genes, and other metabolic disorders compared to their littermates. Additionally, we discovered that HNRNPC facilitated the stability of lymphocyte cytosolic protein 1 (Lcp1) mRNA by binding to the m 6 A motif of LCP1. Overexpression of LCP1 mitigated the inhibition of adipogenesis caused by decreased HNRNPC through modulation of cytoskeletal remodeling. Finally, our findings demonstrate that anti-aging treatments could enhance HNRNPC levels. In conclusion, HNRNPC is positively associated with reduced adipogenesis during aging, and increacing HNRNPC levels through anti-aging treatments highlights its potential as a therapeutic target for addressing metabolic imbalances in adipose tissue related to aging.

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Section: Lcp1 Is the Potential Target Of Hnrnpcmentioning

confidence: 81%

m6A Reader HNRNPC Facilitates Adipogenesis by Regulating Cytoskeletal Remodeling through Enhanced Lcp1 mRNA Stability

2024

Aging dis

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“…Eventually, this process leads to the deposition of a non-compliant, fibrotic scar tissue which might hamper the organ pump function by impairing CMs contractile activity or the electrical conductance [ 1 ] . The biomechanical stress associated with pathological ECM remodelling also modifies the transcriptional and post-transcriptional landscape of cardiac cells [ 33 ] .…”

Section: Discussionmentioning

confidence: 99%

“…In this context, organ decellularization represents an appealing opportunity to provide tissue-specific properties, but their use is hampered by the lack of donors and interspecies differences. More importantly, to the best of our knowledge, none of the options available on the market so far offers the possibility to generate isogenic models of human disease [ 27, 28, 29,30, 31, 32, 33 ].…”

Section: Introductionmentioning

confidence: 99%

An iPSC-derived bio-inspired scaffold modelling the structure and the effects of extracellular matrix in cardiac fibrosis

Niro,

Fernandes,

Cassani

et al. 2024

Preprint

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Cardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the differentiation of cardiac fibroblasts (cFbs) into myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictive in vitro models of heart fibrosis has so far hampered the search for innovative treatments. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (αSMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblasts in vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere alignment, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis.

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“…The loss of YTHDF2 in the cardiomyocytes of adult mice leads to abnormal cardiac remodeling and cardiac function by disrupting the stability and translation of its m6A-modified target transcripts, suggesting that it plays a role in cardiac homeostasis [ 96 , 97 ]. There is also evidence showing that hnRNPC is up-regulated in the sarcomeric Z-disc and likely plays a role in the pathological remodeling of the extracellular matrix [ 98 ]. Altogether, these data suggest that the interactions between m6A readers and their mRNA targets contribute to maintain cardiomyocyte integrity and cardiac contractile function.…”

Section: Rbps Associated With Cardiomyopathiesmentioning

confidence: 99%

RNA-Binding Proteins in Cardiomyopathies

Shi

2024

JCDD

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The post-transcriptional regulation of gene expression plays an important role in heart development and disease. Cardiac-specific alternative splicing, mediated by RNA-binding proteins, orchestrates the isoform switching of proteins that are essential for cardiomyocyte organization and contraction. Dysfunctions of RNA-binding proteins impair heart development and cause the main types of cardiomyopathies, which represent a heterogenous group of abnormalities that severely affect heart structure and function. In particular, mutations of RBM20 and RBFOX2 are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or hypoplastic left heart syndrome. Functional analyses in different animal models also suggest possible roles for other RNA-binding proteins in cardiomyopathies because of their involvement in organizing cardiac gene programming. Recent studies have provided significant insights into the causal relationship between RNA-binding proteins and cardiovascular diseases. They also show the potential of correcting pathogenic mutations in RNA-binding proteins to rescue cardiomyopathy or promote cardiac regeneration. Therefore, RNA-binding proteins have emerged as promising targets for therapeutic interventions for cardiovascular dysfunction. The challenge remains to decipher how they coordinately regulate the temporal and spatial expression of target genes to ensure heart function and homeostasis. This review discusses recent advances in understanding the implications of several well-characterized RNA-binding proteins in cardiomyopathies, with the aim of identifying research gaps to promote further investigation in this field.

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The mechanical regulation of RNA binding protein hnRNPC in the failing heart

Cited by 11 publications

References 110 publications

m6A Reader HNRNPC Facilitates Adipogenesis by Regulating Cytoskeletal Remodeling through Enhanced Lcp1 mRNA Stability

m6A Reader HNRNPC Facilitates Adipogenesis by Regulating Cytoskeletal Remodeling through Enhanced Lcp1 mRNA Stability

An iPSC-derived bio-inspired scaffold modelling the structure and the effects of extracellular matrix in cardiac fibrosis

RNA-Binding Proteins in Cardiomyopathies

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