Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

Abstract

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.

The local mechanosensitive response of primary cardiac fibroblasts is influenced by the microenvironment mechanics

“…Based on the suggested Piezo1 involvement in cardiac fibroblast differentiation 12 , 23 , we focused our attention on the investigation of the mechanical response of fibroblast-activated phenotype.…”

“…In light of this, we discussed in our previous work the evidence for Piezo1 involvement in the fibrotic mechanism and hypothesized the potential advantages of directly targeting Piezo1 in CFs in the context of cardiac fibrosis 12 . More recently, Piezo1 was confirmed to be an essential mechanosensor for cardiac MFs features, along with its overexpression in stiff environments 23 .…”

“…Several non-selective ion channels are expressed in cardiac fibroblasts, as reviewed in our previous work 12 . However, most of the Transient Receptor Potential (TRP) channels, some of which are also expressed by CFs and historically reported as elements involved in mechanosensory processes, have recently been confirmed to be intrinsically insensitive to membrane stretch 13 .…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…There are some studies about ion channel; for instance, the mechanosensitive ion channel transient receptor potential vanilloid four deletion regulates CF-to-MF transformation to improve harmful remodeling after MI ( Adapala et al, 2020 ; Adapala et al, 2021 ). Piezo1 activates CFs to induce MFs recruitment and excessive ECM deposit ( Braidotti et al, 2022 ), while coronary vascular endothelial sodium channel activation promotes cardiac fibrosis and dysfunction ( Hill et al, 2022 ). Further, embryonic CFs of mice with mitochondrial Ca 2+ uniporter deletion are more sensitive to Ca 2+ overload than normal CFs ( Huo et al, 2020 ).…”

Cardiomyocyte intercellular signalling increases oxidative stress and reprograms the global‐ and phospho‐proteome of cardiac fibroblasts

“…Principal component analysis revealed distinct clustering of Ctrl-CM-CF and TGFβ-CM-CF (Figure 2d). Pairwise comparative analysis revealed significant dysregulation (Student's T-test, p < 0.05) of fibrosis associated proteins including COL6A2 (Williams et al, 2022), AGTRAP (Subbaiah et al, 2022), LOXL4 (González-Santamaría et al, 2016), and PIEZO1 (Braidotti et al, 2022) in TGFβ-CM-CF (Figure 2e, Table S4). Analysis of significantly dysregulated components (Student's T-test, p < 0.05) using Gene Ontology enrichment (g:Profiler and Reactome (Figure 2f)) revealed significant alteration of protein metabolism, signalling, lysosome, carbohydrate metabolism, and translational regulation.…”