American journal of physiology. Cell physiology最新文献

{"title":"The stiffness of extracellular matrix (ECM) in regulating cellular metabolism.","authors":"Boyang Zha, Chunlei Zhang, Congying Wu","doi":"10.1152/ajpcell.00913.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00913.2024","url":null,"abstract":"<p><p>Cells interact dynamically with the extracellular matrix (ECM), which provides both structural support and biochemical signals that regulate various cellular processes. Among these, the mechanical properties of the ECM, particularly stiffness, play a crucial role in governing cell differentiation, migration, and survival. Recent studies have highlighted the intricate relationship between ECM stiffness and cellular metabolism, influencing key pathways such as glucose, lipid and amino acid metabolism. This review explores how ECM stiffness modulates these metabolic processes, emphasizing the underlying mechano-transduction mechanisms. Additionally, we discuss emerging techniques that enable the investigation of ECM-mediated force sensing and response, providing new insights to the mechanoregulation of metabolism and its implications in disease and therapy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular protection by young circulating extracellular vesicles ameliorates aging-related pulmonary fibrosis.","authors":"Fiorenza Gianì, Benjamin B Roos, Patrick A Link, Bharath Somasundram, Sara Dresler, Enrico Sciacca, Carlo Vancheri, Naureen Javeed, Giovanni Ligresti, Daniel J Tschumperlin, Nunzia Caporarello","doi":"10.1152/ajpcell.00022.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00022.2025","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a fatal aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA approved anti-fibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression. Unexplored, however, are the modalities to restore vascular abnormalities associated with progressive lung fibrosis, representing a critical gap to effective treatments for IPF. In this study, we demonstrate that circulating extracellular vesicles (cEVs) isolated from young mice are capable of reversing the aging-associated transcriptional alterations of the pulmonary vasculature, reducing transcripts associated with innate immunity, oxidative stress and senescence, while simultaneously increasing transcripts linked to endothelial identity. Using the bleomycin model of persistent lung fibrosis in aged mice, we then demonstrate that the pre-treatment with cEVs improves the vascular response to injury and attenuates lung fibrosis progression, as demonstrated by reduced lung collagen content and preserved vascular network and lung architecture. These findings support the efficacy of interventions targeting endothelial aging-associated transcriptional alterations, such as young cEV delivery, in mitigating pulmonary fibrosis progression in animal models of persistent fibrosis and indicate the potential benefits of combined therapies that simultaneously address vascular and non-vascular aspects of IPF.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural compounds and strategies for fighting against drug resistance in cancer: a special focus on phenolic compounds and microRNAs.","authors":"Nina Petrović, Ivana Z Matić, Tatjana Stanojković","doi":"10.1152/ajpcell.00428.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00428.2024","url":null,"abstract":"<p><p>Bioactive phytochemicals, phenolic compounds, terpenoids, and alkaloids, exert antioxidative, anti-inflammatory, antigenotoxic, and anticancer effects, simultaneously showing minimal or no toxicity on normal, healthy cells. Phytochemicals targeting various signaling pathways and multiple mechanisms underlying intrinsic and acquired multidrug resistance (MDR) in cancer cells make them invaluable tools for the development of novel strategies for fighting against anticancer drug resistance in different cancer types, which is one of the ultimate goals of modern oncology research. As MDR is described to be a simultaneous development of resistance to multiple drugs with different chemical structures, mechanisms of action, and targets it is not surprising that multiple factors, such as genetic and epigenetic changes, as well as non-coding RNAs, including microRNAs may significantly contribute to the development MDR in cancer cells, and its targeting and modulation of their expression to sensitize cells to treatment. This review implies that some natural compounds, such as curcumin, resveratrol, kaempferol, allicin, and quercetin have the potential to interact with highly oncogenic and/or proinflammatory miRNAs such as miR-21/155/663/146a significantly influencing the response to cancer therapy. The article aims to point out how natural compounds may be used accompanied by miRNAs mimics or miRNA inhibitors to treat specific cancer types and subtypes to overcome multidrug resistance. The main challenge is to determine the proper doses and concentrations of both, miRNAs and compounds.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enteroendocrine cells regulate intestinal barrier permeability.","authors":"Jennifer G Nwako, Sparsh D Patel, Taevon J Roach, Saanvi R Gupte, Samara G Williams, Anne Marie Riedman, Heather A McCauley","doi":"10.1152/ajpcell.01077.2024","DOIUrl":"10.1152/ajpcell.01077.2024","url":null,"abstract":"<p><p>The intestinal epithelial barrier is essential for nutrient absorption and protection against ingested pathogens and foreign substances. Barrier integrity is maintained by tight junctions, which are sensitive to inflammatory signals, thus creating a feed-forward loop with an increasingly permeable barrier that further drives inflammation and is the hallmark of inflammatory bowel disease. There are currently no therapeutic strategies to improve the intestinal epithelial barrier. We hypothesized that enteroendocrine cells may play an unappreciated role in maintaining barrier integrity. To test this hypothesis, we seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins. We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like \"stem\" and villus-like differentiated cultures. In addition, exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine-tyrosine (PYY), and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor. Surprisingly, these improvements in barrier function occurred largely independently of changes in protein abundance of junctional proteins zona occludens 1, occludin, and claudin-2. These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier.<b>NEW & NOTEWORTHY</b> There are no therapies that directly improve the permeability of the intestinal epithelial barrier. This work uses a human intestinal epithelial model system to demonstrate that sensory enteroendocrine cells are necessary for healthy barrier function and that two of their secreted products, peptide YY and somatostatin, are sufficient to improve barrier function at homeostasis and in the presence of inflammatory cytokines. This could provide novel treatments for strengthening the epithelial barrier in human gastrointestinal disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1501-C1508"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The long road to Ithaca: a physiologist's journey.","authors":"Sadis Matalon","doi":"10.1152/ajpcell.00030.2025","DOIUrl":"10.1152/ajpcell.00030.2025","url":null,"abstract":"<p><p>It was an honor to be asked to deliver the Walter B. Cannon Lecture during the 2024 American Physiological Summit meeting. Dr. Cannon served as president of the American Physiological Society from 1914-1916. He coined the term \"fight or flight\" to describe an animal's response to threats and the concept of Homeostasis. He was the consummate physician-scientist, an outstanding mentor and teacher, a prolific writer, and a humanitarian. The title of my lecture is based on a poem entitled \"Ithaca,\" written by the Greek poet C. P. Cavafy, who recounts the 10 yr travels of Ulysses, from Troy to his home, Ithaca. Odysseus had to overcome many obstacles to survive this long journey. Like Odysseus, I encountered myriad of professional and health problems. But, I also have experienced the thrill of contributing to scientific knowledge, the satisfaction of watching my mentees develop into independent scientists, the excitement of teaching respiration physiology to medical and professional students, and the pleasure of being of service to my discipline by serving as Editor of the American Journal of Physiology-Lung Cellular and Molecular Physiology and of Physiological Reviews. During my career, I have been interested in identifying the basic mechanisms by which oxidant gases and pathogens damage the blood gas barrier resulting in acute and chronic lung injury. In this brief review, I summarize the results of current studies implicating free heme as a major mediator of acute lung injury and our efforts to develop recombinant forms of human hemopexin, as a countermeasure.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1526-C1534"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel lncRNA ABCE1-5 regulates pulmonary fibrosis by targeting KRT14.","authors":"Shuwei Gao, Yanqiu Wei, Chen Li, Bingbing Xie, Xinran Zhang, Ye Cui, Huaping Dai","doi":"10.1152/ajpcell.00374.2024","DOIUrl":"10.1152/ajpcell.00374.2024","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive and degenerative interstitial lung disease characterized by complex etiology, unclear pathogenesis, and high mortality. Long noncoding RNAs (lncRNAs) have been identified as key regulators in modulating the initiation, maintenance, and progression of pulmonary fibrosis. However, the precise pathological mechanisms through which lncRNAs are involved in IPF remain limited and require further elucidation. A novel lncABCE1-5 was identified as significantly decreased by an ncRNA microarray analysis in our eight IPF lung samples compared with three donor tissues and validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis in clinical lung samples. To investigate the biological function of ABCE1-5, we performed loss- and gain-of-function experiments in vitro and in vivo. LncABCE1-5 silencing promoted A549 cell migration and A549 and bronchial epithelial cell line (BEAS-2B) cell apoptosis while enhancing the expression of proteins associated with extracellular matrix deposition, whereas overexpression of ABCE1-5 partially attenuated transforming growth factor-beta (TGF-β)-induced fibrogenesis. Forced ABCE1-5 expression by intratracheal injection of adeno-associated virus 6 revealing the antifibrotic effect of ABCE1-5 in bleomycin (BLM)-treated mice. Mechanistically, RNA pull-down (RPD)-mass spectrometry and RNA immunoprecipitation assay demonstrated that ABCE1-5 directly binds to keratin14 (krt14) sequences, potentially impeding its expression by perturbing mRNA stability. Furthermore, decreased ABCE1-5 levels can promote krt14 expression and enhance the phosphorylation of both mTOR and Akt; overexpression of ABCE1-5 in BLM mouse lung tissue significantly attenuated the elevated levels of p-mTOR and p-AKT. Knockdown of krt14 reversed the activation of mTOR signaling mediated by ABCE1-5 silencing. Collectively, the downregulation of ABCE1-5 mediated krt14 activation, thereby activating mTOR/AKT signaling, to facilitate pulmonary fibrosis progression in IPF.<b>NEW & NOTEWORTHY</b> In the present study, our data first reveal that a novel lncRNA ABCE1-5 could inhibit pulmonary fibrosis through interacting with krt14 and negative regulation of its expression, and indicated ABCE1-5 also regulates the phosphorylation of mTOR and Akt, thus acting on extracellular matrix remodeling in lung fibrosis procession. These results suggest that novel molecules within the ABCE1-5-krt14-mTOR axis may serve as potential candidates for clinical application in IPF.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1487-C1500"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in synthetic Notch receptors for biomedical application.","authors":"Luyao Song, Qinmeng Zhang, Hairu Sui, Chenlu Gao, Zhiwei Jiang","doi":"10.1152/ajpcell.00659.2024","DOIUrl":"10.1152/ajpcell.00659.2024","url":null,"abstract":"<p><p>The synthetic Notch receptor has emerged as a potent tool for precisely modulating cellular functions. It constitutes a receptor system rooted in the Notch signaling pathway. SynNotch receptors, coupled with downstream transcription programs, hold promise for organoid and three-dimensional (3-D) tissue construction. In addition, it enables the tracking and visualization of intercellular communication. Moreover, engineering SynNotch cells to carry specific receptors markedly enhances the efficacy and safety of immunotherapy. This review delineates the subdomains and tunable mechanisms of SynNotch, summarizing four core modes of combinatorial multiplexing potentially pivotal for regulating SynNotch cell functions. Furthermore, this review summarizes the multifaceted applications, advantages, and limitations of SynNotch, offering fresh insights into its future biomedical utilization.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1473-C1486"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance exercise and mechanical overload upregulate vimentin for skeletal muscle remodeling.","authors":"Joshua S Godwin, J Max Michel, Cleiton A Libardi, Andreas N Kavazis, Christopher S Fry, Andrew D Frugé, Mariah McCashland, Ivan J Vechetti, John J McCarthy, C Brooks Mobley, Michael D Roberts","doi":"10.1152/ajpcell.01028.2024","DOIUrl":"10.1152/ajpcell.01028.2024","url":null,"abstract":"<p><p>We adopted a proteomic and follow-through approach to investigate how mechanical overload (MOV) potentially affects novel targets in skeletal muscle, and how a perturbation in this response could potentially affect the adaptive response. First, we determined that 10 wk of resistance training in 15 college-aged females increased sarcolemmal-associated protein content (+10.1%, <i>P</i> < 0.05). Sarcolemmal protein isolates were then queried using mass spectrometry-based proteomics, ∼10% (38/387) of proteins putatively associated with the sarcolemma or extracellular matrix (ECM) were upregulated (>1.5-fold, <i>P</i> < 0.05), and one target (intermediate filament vimentin; VIM) warranted further investigation due to its correlation to myofiber hypertrophy (<i>r</i> = 0.652, <i>P</i> = 0.009). VIM expression was then examined in 4-mo-old C57BL/6J mice following 10 and 20 days of plantaris MOV via synergist ablation. Relative to Sham (control) mice, VIM mRNA and protein content was significantly higher in MOV mice, and immunohistochemistry indicated that VIM predominantly resided in the ECM. MOV experiments were replicated in Pax7-DTA (satellite cell depleted) mice, which reduced VIM in the ECM by ∼74%. A third MOV experiment was performed in C57BL/6 mice intramuscularly injected with either AAV9-scrambled (control) or AAV9-VIM-shRNA. Although VIM-shRNA mice possessed lower VIM in the ECM (∼45%), plantaris masses in response to MOV were similar between groups. However, VIM-shRNA mice possessed smaller and more centrally nucleated MyHC_emb-positive fibers in response to MOV. In summary, skeletal muscle VIM appears to be enriched in the ECM following MOV, satellite cells may regulate its expression, and a disruption in expression during MOV leads to an excessive regenerative phenotype.<b>NEW & NOTEWORTHY</b> Our highly integrative approach suggests that skeletal muscle vimentin seems to function as a mechanosensitive protein that becomes enriched in the extracellular matrix following MOV. Satellite cells may play a role in regulating their expression, and an exaggerated regenerative response occurs when vimentin expression becomes dysregulated during mechanical overload. Although these data implicate vimentin in aiding with tissue remodeling following MOV, more data are needed to determine the functional ramifications of VIM response deficiencies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1509-C1525"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular circadian clock of eosinophils: a potential therapeutic target for asthma.","authors":"Julia Teppan, Thomas Bärnthaler, Aitak Farzi, Hannah Durrington, Gael Gioan-Tavernier, Hazel Platt, Peter Wolf, Akos Heinemann, Eva Böhm","doi":"10.1152/ajpcell.00149.2025","DOIUrl":"10.1152/ajpcell.00149.2025","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory airway disease exhibiting time-of-day variability in symptoms and severity. Eosinophils, pivotal players and biomarkers in asthma, are regulated by the molecular circadian clock. This study aimed to investigate the impact of the molecular circadian clock on eosinophil effector function and its potential as a diagnostic biomarker and therapeutic target. We monitored clock proteins by flow cytometry in peripheral blood eosinophils from participants with mild asthma over a 24-h period. The observed decreased protein levels were confirmed in a cohort of patients with moderate asthma. To assess the interaction between inflammation and the molecular circadian clock, eosinophils were stimulated with patients' sera, inflammatory mediators, and clock-modulating ligands. The therapeutic potential of the inverse retinoic acid receptor-related-related orphan receptor (ROR) agonist SR1001 was evaluated in vitro and in a murine model of allergen-induced airway inflammation. Altered protein levels of circadian locomotor output cycles kaput (CLOCK), Brain and muscle Arnt-like protein-1 (BMAL1), REV-ERBs, and RORs in eosinophils from participants with asthma reflected the disease severity and allergy status of the patients. Mimicking an inflammatory environment in vitro resulted in similar changes. Blocking C-C chemokine receptor type 3 (CCR3)/ERK and epidermal growth factor receptor (EGFR) signaling with an inverse ROR agonist SR1001 reset the molecular circadian clock in eosinophils and exhibited anti-inflammatory effects by inhibiting eosinophil migration in vitro. In addition, we confirmed the therapeutic potential of the clock-modulating SR1001, bronchoprotective effects in two in vivo models. This study suggests that clock proteins could serve as therapeutic targets in asthma. Pharmacological inhibition of ROR signaling demonstrated significant anti-inflammatory and bronchoprotective properties, indicating its potential as a novel treatment strategy for asthma and other eosinophilic diseases.<b>NEW & NOTEWORTHY</b> Our findings highlight the role of the circadian system as an immunomodulatory regulator, biomarker, and therapeutic target in chronic inflammatory diseases. The observed inflammation-driven downregulation of the molecular circadian clock may also represent a key mechanism that triggers the switch from homeostatic to pro-inflammatory eosinophils. Furthermore, we demonstrate for the first time that pharmacologic inhibition of ROR resets the molecular circadian clock and induces anti-inflammatory and lung-protective effects without disrupting circadian rhythms.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1394-C1408"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological function of cyclic nucleotide phosphodiesterases in atrial myocytes and their potential as therapeutic targets for atrial fibrillation.","authors":"Matthew John Read, Andreas Koschinski, Samuel Jitu Bose, Rebecca A B Burton","doi":"10.1152/ajpcell.00782.2024","DOIUrl":"10.1152/ajpcell.00782.2024","url":null,"abstract":"<p><p>Cyclic nucleotide hydrolyzing phosphodiesterases (PDEs) are key regulators of cyclic nucleotide (e.g., cAMP and cGMP) signaling. Here, we examine the role of PDEs in the physiology of atrial myocytes (AMs), the pathogenesis of atrial fibrillation (AF), and the potential of PDEs as therapeutic targets for AF. PDE1-5 and 8 are present and functional in AMs. PDE2-4 are important regulators of AM contraction but their role beyond atrial contractility is unclear. The role of PDE1,5 and 8 in healthy AMs is unknown but of interest because of their roles in ventricular myocytes. We propose that PDE2-5 and PDE8 are potential targets to prevent the triggering of AF considering their effects on Ca²⁺ handling and/or electrical activity. PDE1-5 are possible targets to treat patients with paroxysmal or persistent AF caused by pulmonary vein automaticity. PDE8B2 is a possible target for patients with persistent AF due to its altered expression. Research should aim to identify the presence, localization, and function of specific PDE isoforms in human atria. Ultimately, the paucity of PDE isoform-specific small molecule modulators and the difficulty of delivering PDE-targeted medications or therapies to particular cell types limit current research and its application.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1423-C1454"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}