American journal of physiology. Cell physiology最新文献

{"title":"The Hidden Proteome of Cutaneous Repair: Emerging Roles of ncRNA-Encoded Micropeptides.","authors":"Sibei Tang, Li Li, Hanyu Dou, Xiaolei Ding, Dongqing Li, Dongsheng Jiang","doi":"10.1152/ajpcell.90039.2026","DOIUrl":"10.1152/ajpcell.90039.2026","url":null,"abstract":"<p><p>The molecular mechanisms governing cutaneous repair have been largely understood through transcriptional and post-transcriptional regulatory networks. Recent discoveries, however, have challenged the long-held assumption that noncoding RNAs (ncRNAs) function exclusively as regulatory transcripts. Advances in translatomics have revealed that a subset of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) encode bioactive micropeptides, uncovering a hidden proteome involved in tissue repair. In this mini-review, we discuss the established and potential roles of ncRNA-derived micropeptides in processes relevant to cutaneous repair, including re-epithelialization, fibroblast plasticity and matrix remodeling, inflammatory resolution and vascular repair. Rather than acting as isolated molecular effectors, these micropeptides operate across multiple biological scales, from intracellular protein signaling and cell-intrinsic programs to tissue remodeling and the broader repair microenvironment. We further highlight the emerging concept that a single ncRNA locus can generate distinct RNA- and peptide-mediated functions, thereby expanding the regulatory capacity of the noncoding genome. Finally, we discuss key unanswered questions, including what licenses context-specific micropeptide translation during tissue repair and how RNA and micropeptide outputs cooperate to shape repair outcomes. Together, these advances support an emerging conceptual framework in which the ncRNA-encoded hidden proteome constitutes an additional regulatory layer in cutaneous repair, providing new insights into unconventional mechanisms of tissue repair and potential opportunities for therapeutic intervention.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036171","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":"Establishment of a cell line-based 3D co-culture model of the endometrium for studying endometrial receptivity.","authors":"Konstantina Kyriakopoulou, Mariam A Heukamp, Marco Franchi, Ulla Obermeyer, Evelin Fuchs, Nancy Espinoza-Sanchez, Johanna Hellmold, Lars Hanker, Martin Götte, Heba M El-Shorafa","doi":"10.1152/ajpcell.00626.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00626.2025","url":null,"abstract":"<p><p>A receptive endometrium is essential for successful embryo implantation, yet its dynamic cellular and molecular features remain poorly understood due to limitations in current in vitro models. We aimed to establish a 3D co-culture endometrial model mimicking physiological conditions, characterizing its response to varied culture conditions using receptivity-associated gene expression profiling. Epithelial Ishikawa or RL95-2 cells were layered above stromal St-T1b cells separated by Matrigel and cultured in different media (growth factor-reduced, serum-containing standard, cytokine-supplemented and EGF-supplemented) or exposed to hormonal stimuli (E2, P4, cAMP) over a 10-day differentiation period. Our model effectively recapitulates the layered structure of the endometrium, as confirmed by scanning electron microscopy and immunofluorescence. Transcriptional analysis of fertility-associated markers revealed media- and cell line-dependent alterations of key receptivity markers; In standard media gene expression alterations occurred for HEY1 in both, but for HEY2 solely in the Ishikawa model and EDNRB only in the RL95-2 model, in cytokine-supplemented media for LIF and TAGLN in both models, while HPSE only in RL95-2 models and DPP4 and HEY1 only in Ishikawa models. Notably, the long-term hormonal treatment triggered a transcriptomic signature, especially in the RL95-2 model that closely correlates to the clinically determined one at the window of implantation (WOI). We conclude that our in vitro model reflects the phenotypic and transcriptional dynamics of the in vivo endometrium and responds distinctly to external stimuli. It serves as a robust platform to study endometrial receptivity mechanisms and holds potential for future applications in infertility and implantation research.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023708","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":"Integrating and Orchestrating Multiple Components of Skeletal Muscle Injury and Regeneration.","authors":"Steven S Segal","doi":"10.1152/ajpcell.00873.2025","DOIUrl":"10.1152/ajpcell.00873.2025","url":null,"abstract":"<p><p>As a soft tissue comprising nearly half of body mass, skeletal muscle is vulnerable to injury from many sources. Healthy muscle can regenerate from resident stem cells known as satellite cells (SCs). During homeostasis, individual SCs reside within a niche sandwiched between basal lamina (BL) and sarcolemma, dispersed along the periphery of mature myofibers. The SC niche abuts capillaries embedded in extracellular matrix (ECM) containing fibroblasts and immune cells. With integral roles for each component of muscle tissue, cellular responses to injury are integrated and orchestrated during regeneration. Following physical trauma, chemical damage, or myotoxin exposure, inflammation ensues with efferocytosis removing debris and creating space for new growth. Residual BL selectively guide regeneration of myofibers, capillaries, and nerves. SCs transition from quiescence to activation, proliferate as myoblasts, differentiate into myocytes, fuse into multinucleated myotubes (or undergo self-renewal) and return to quiescence while nascent myofibers mature. In parallel, fibroadipogenic progenitor cells transiently proliferate to support regeneration of healthy tissue. Endothelial tip cells sprout filopodia to orient capillary growth with microvascular networks remodeling as muscle blood flow is restored. Following Wallerian degeneration, axons extend filopodia to orient their regrowth within the neurolemma along tracks of endothelial cells; cues from myofibers guide reinnervation of neuromuscular junctions. Coordinated through autocrine, paracrine, and juxtacrine signaling with guidance from the immune system and ECM, interactions between myogenesis, angiogenesis, and reinnervation provide synergistic support as muscle structure and function are restored. Failure of regeneration leads to fibrosis, loss of strength, and impaired mobility.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987740","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":"Role of cardiac ion pumps, channels, and exchangers on regulation of mitochondrial bioenergetics.","authors":"David F Stowe, Amadou K S Camara","doi":"10.1152/ajpcell.00305.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00305.2026","url":null,"abstract":"<p><p>Membrane ion pumps and channels are essential key players in intracellular function and communication with other cells, e.g., nutrient uptake and bioelectrical communication. The cation exchangers Na⁺, H⁺, Ca²⁺ and K⁺ do more than simply rebalance ions and maintain ion homeostasis; they play crucial roles in modulating overall cellular bioenergetics. This review aims to describe how these cation gradients are formed and maintained by examining the ion flux mediated by each pump, channel, and exchanger and by integrating their functions across the cell and mitochondrial membranes. Most of this information is derived from the large amount of work in cardiac muscle cells where fluctuations in ion fluxes occur second by second. First is presented a review of the sarcolemmal and sarco(endo)plasmic reticular ion pumps, channels, and exchangers because mitochondrial ion fluxes are affected by the cytosolic ion concentrations. Then mitochondrial ion fluxes regulated by the mitochondrial ion pumps, channels, and exchangers are discussed. There are prior excellent reviews on mitochondrial cation fluxes, so the goal is to update the narrative with more recent publications that expand our understanding, with some controversies, of cell and mitochondrial cation fluxes on regulating a multitude of cell and organelle functions. Updates are furnished on the putative identity and function of the four major mitochondrial cation exchangers. Also, an emphasis is placed on updating the role of transmembrane ion fluxes on impacting mitochondrial bioenergetics by altering the proton motive force and oxidative phosphorylation. A few important historical reports are included with the recent studies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987684","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":"Uncertainty-Aware Modeling in Integrated Epithelial Transport Networks.","authors":"Pooya Razzaghi Khamesi, Victoria Makrides, Vartan Kurtcuoglu","doi":"10.1152/ajpcell.00068.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.00068.2026","url":null,"abstract":"<p><p>While computational mechanistic models can provide insight into the coupled transport of substrates through complex networks of membrane transporters and channels, commonly used deterministic models are often constrained by uncertainty in model structure and in parameters derived from sparse and limited data. As a result, models may lack generalizability, particularly when high confidence is required for testing mechanistic hypotheses. Here we present, as a proof-of-principle, a Bayesian framework for uncertainty-aware modeling that enables deeper mechanistic insight and more reliable hypothesis testing. As an illustrative example, we applied this framework to the rat choroid plexus epithelium, a tissue characterized by a coupled, nonlinear transport network for which quantitative data are limited. Using a thermodynamics-based model of coupled Na+, K+, Cl-, HCO3-, and water transport, we compared deterministic parameter assignment with Bayesian inference. The Bayesian framework yielded physiologically plausible parameter distributions for 14 cellular, transporter, and channel parameters, quantified predictive uncertainty and data informativeness, and enabled assessment of model structural adequacy. We show how the framework distinguishes between model-data mismatch arising from parameter uncertainty and that due to structural limitations, and identifies where additional data would reinforce predictive reliability. Predictions based on data-informed parameter ensembles reproduced expected stoichiometries (e.g., K⁺:Cl⁻ ≈ 1:2) and revealed testable mechanistic couplings, including constraints on NKCC1 flux imposed by Na⁺/K⁺-ATPase capacity, that are not accessible through nominal deterministic fits. Overall, this work provides a systematic approach for assessing, refining, and interpreting mechanistic models of epithelial transport under uncertainty that is intrinsic to biological systems.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928763","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":"Modulation of cyst growth in autosomal dominant polycystic kidney disease: mechanistic insights and therapeutic opportunities.","authors":"Raluca Ursu, Bjoern Buchholz, Kathrin Skoczynski","doi":"10.1152/ajpcell.00222.2026","DOIUrl":"10.1152/ajpcell.00222.2026","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney disorders and is characterized by the progressive formation and expansion of fluid-filled cysts, ultimately leading to kidney failure. Although caused by reduced dosage of the polycystin proteins, the disease phenotype arises from a broad disruption of epithelial physiology rather than a single linear pathway. Loss of polycystin function destabilizes epithelial homeostasis and sensitizes cyst-lining cells to proliferative and secretory cues. A central consequence is the emergence of a self-reinforcing signaling environment in which cyclic AMP, Ca²⁺, and purinergic pathways amplify one another, promoting chloride-driven fluid secretion and epithelial proliferation. In parallel, cyst epithelia exhibit disturbed cell turnover, including altered proliferation, apoptosis, autophagy, and ferroptotic stress, which reshape luminal architecture and sustain a prosecretory microenvironment. Metabolic reprogramming, characterized by enhanced glycolysis, mitochondrial dysfunction, and redox imbalance, provides energetic support for these processes and further strengthens proliferative and secretory signaling. Hypoxia-inducible factor-1α (HIF-1α) integrates hypoxic, metabolic, and mechanical cues into transcriptional programs that reinforce cyst expansion. This review synthesizes these interconnected mechanisms and highlights potential therapeutic strategies, including restoration of polycystin expression, modulation of cAMP and purinergic signaling, inhibition of chloride secretion, metabolic targeting, and HIF-1α pathway intervention. Together, these insights support a model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs. Effective disease modification will likely require multinodal therapeutic approaches that address this integrated network.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C605-C622"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618139","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":"Hypoxic eNOS uncoupling as a consequence of DHFR downregulation in various human endothelial cell lines: the crucial role of the BH₄ regeneration pathway.","authors":"Anna Janaszak-Jasiecka, Adrianna Radulska, Anna Siekierzycka, Agata Płoska, Tomasz Borkowski, Iwona T Dobrucki, Rafał Bartoszewski, Leszek Kalinowski","doi":"10.1152/ajpcell.00171.2026","DOIUrl":"10.1152/ajpcell.00171.2026","url":null,"abstract":"<p><p>Tetrahydrobiopterin (BH₄) is an essential cofactor for endothelial nitric oxide synthase (eNOS), which produces nitric oxide (NO) to maintain vascular homeostasis. When BH₄ is deficient, eNOS becomes uncoupled, generating superoxide ([Formula: see text]) instead of NO, contributing to endothelial dysfunction and cardiovascular disease. The cellular BH₄ concentration is determined by its de novo synthesis via GTP cyclohydrolase I (GTPCH), oxidation of BH₄ to BH₂, and the regeneration of BH₄ from BH₂ by dihydrofolate reductase (DHFR). A diminished BH₄/BH₂ ratio, often due to DHFR dysregulation, promotes eNOS uncoupling. This study investigates how hypoxia affects eNOS activity and NO bioavailability in human endothelial cells (ECs) derived from various vascular beds. We show that hypoxia downregulates eNOS and DHFR, impairs BH₄ regeneration, and induces eNOS uncoupling in all human EC types tested. We also demonstrate that human ECs exhibit low basal BH₄ levels, which may result from limited GTPCH expression; consequently, the BH₄/BH₂ ratio appears to depend substantially on DHFR activity. Importantly, we show for the first time that BH₄-dependent regulation of eNOS uncoupling varies between ECs derived from distinct vascular beds. This variability is driven by cell-type-specific differences in the relative levels of eNOS and DHFR under hypoxia. In particular, human aortic endothelial cells (HAECs) display high eNOS expression and low DHFR levels, making them especially prone to hypoxic eNOS uncoupling. These findings suggest that certain vascular beds may be intrinsically more susceptible to hypoxia-induced endothelial dysfunction, driven by greater eNOS uncoupling that depends on DHFR activity, highlighting DHFR as a potential therapeutic target.<b>NEW & NOTEWORTHY</b> This study identifies DHFR-dependent BH₄ regeneration as the key determinant of eNOS coupling in human endothelial cells with intrinsically low BH₄ levels. We show that hypoxia disrupts this pathway, leading to eNOS uncoupling in a vascular bed-specific manner. Notably, human aortic endothelial cells are particularly susceptible due to high eNOS and low DHFR expression, highlighting DHFR as a potential therapeutic target in hypoxia-driven endothelial dysfunction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C653-C663"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688369","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":"Combination therapy of RAS inhibition and glucagon-like peptide-1 receptor agonist improves a marker of kidney fibrosis in people with type 2 diabetes.","authors":"Alexandra L Møller, Stefanie Thöni, Felix Keller, Samir Sharifli, Federica Genovese, Morten Karsdal, Daniel G K Rasmussen, Gert Mayer","doi":"10.1152/ajpcell.00526.2025","DOIUrl":"10.1152/ajpcell.00526.2025","url":null,"abstract":"<p><p>In type 2 diabetes (T2D), kidney fibrosis drives the progression of chronic kidney disease (CKD) and kidney failure. Lower urinary levels of collagen type III degradation (C3M), a biomarker of extracellular matrix (ECM) turnover, have been associated with CKD progression. We investigated the effect of combination therapy with renin-angiotensin system inhibition (RASi) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) on urinary C3M levels in people with T2D. Urinary C3M was measured using the nordicC3M ELISA in 229 participants from the Drug Combinations for Rewriting Trajectories of Renal Pathologies in T2D (DC-ren) project. Longitudinal changes in urinary C3M were analyzed using linear regression stratified by treatment group. Risk of kidney disease progression according to baseline urinary C3M was evaluated using Kaplan-Meier analysis. The kidney endpoint was defined as >10% decline in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m². Combination therapy (RASi + GLP-1 RA) was associated with higher urinary C3M levels compared with RASi monotherapy (<i>P</i> = 0.036). Urinary C3M was positively associated with future eGFR, with a steeper slope in the combination therapy group than in the RASi monotherapy group (<i>P</i> < 0.001). Low baseline urinary C3M was associated with a higher risk of kidney disease progression (<i>P</i> = 0.022). In people with T2D receiving combination therapy with RASi + GLP-1 RA, urinary C3M levels remained stable, whereas levels decreased with RASi monotherapy, suggesting altered kidney ECM turnover.<b>NEW & NOTEWORTHY</b> Urinary C3M is a dynamic biomarker of ECM turnover with pharmacodynamic relevance in kidney disease. Previous studies in diabetic and nondiabetic kidney disease have shown that therapeutic interventions can increase urinary C3M levels. Here, compared with RASi monotherapy, GLP-1 RA-based combination therapy with RASi was associated with a more favorable longitudinal urinary C3M trajectory and an altered association between urinary C3M and kidney function in type 2 diabetes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C825-C833"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762741","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":"Subcellular regulation of ferroptosis: roles of individual intracellular organelles and cross talk.","authors":"Chanon Piamsiri, Judith K Gwathmey, Lai-Hua Xie","doi":"10.1152/ajpcell.00334.2026","DOIUrl":"10.1152/ajpcell.00334.2026","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. Emerging evidence indicates that susceptibility to ferroptosis is not governed solely by cytosolic signaling pathways, but instead results from the coordinated actions of multiple intracellular organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), and lipid droplets (LDs). Mitochondria play dual roles in ferroptosis by integrating metabolic activity, redox balance, and mitochondrial quality control; thereby influencing reactive oxygen species (ROS) generation and lipid peroxidation. Lysosomes regulate ferroptotic sensitivity through iron mobilization, inter-organelle iron transfer, lysosomal redox activity/lipid peroxidation, lysosomal signaling hub, and ferritinophagy. The ER contributes to ferroptosis by coordinating lipid biosynthesis, membrane polyunsaturated fatty acid composition, and unfolded protein response signaling, as well as by disrupting antioxidant defenses and iron homeostasis, especially during ER stress. Lipid droplets function as dynamic lipid reservoirs that buffer oxidizable fatty acids or, upon mobilization, supply substrates that fuel ferroptosis-associated lipid peroxidation. Here, we provide a comprehensive review of current mechanistic insights and recent advances in organelle-specific regulation and inter-organelle cross talk during ferroptosis, highlighting emerging therapeutic opportunities and key experimental challenges. An integrated understanding of this multi-organelle regulatory network is essential for modulating ferroptosis in human diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C705-C721"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618140","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":"β₂-Adrenergic receptor disruption exacerbates cardiac injury and fibroblast activation in a female mouse model of Takotsubo cardiomyopathy.","authors":"Bruno Sanches, Fernanda Tupini, Fernando Espanhol, Pedro Augusto Carvalho Costa, Gabriel Matos Nogueira, Iago Pinheiro, Fernando Souza-Neto, Alexander Birbrair, Pedro Pires Goulart Guimarães, Marina G M Castor, Jop H van Berlo, Silvia Guatimosim","doi":"10.1152/ajpcell.00087.2026","DOIUrl":"10.1152/ajpcell.00087.2026","url":null,"abstract":"<p><p>Takotsubo cardiomyopathy (TTC) is an acute stress-induced cardiac syndrome that predominantly affects women and is driven by surges in catecholamines that excessively activate β-adrenergic receptors (βARs). Although β₁AR signaling mediates much of the injury, β₂ARs have recognized cytoprotective roles in other cardiac settings, yet their contribution to TTC-associated remodeling remains unclear. To address this gap, we induced a TTC-like phenotype in female wild-type (WT) and β₂AR-deficient (β₂AR^-/-) mice with a single high dose of isoproterenol (ISO). After ISO injection, β₂AR^-/- mice exhibited exacerbated myocardial injury, characterized by greater hypertrophy and higher levels of apoptosis and necrosis compared with WT/ISO mice. This heightened injury was accompanied by a more robust inflammatory response, including increased inflammatory score, enhanced CD68⁺ macrophage infiltration, and marked recruitment of CCR2⁺MHC-II^low monocytes. β₂AR^-/-/ISO hearts also displayed more extensive interstitial fibrosis. Because fibrosis is a key driver of long-term functional decline, we isolated cardiac fibroblasts (CFs) and characterized their activation state. CFs from β₂AR^-/-/ISO hearts displayed a significantly higher percentage of α-SMA⁺ cells, increased Collagen 3 and MMP-2 staining, along with upregulation of profibrotic genes (<i>Col1a1</i>, <i>Col3a1</i>, <i>Fap</i>). Functionally, β₂AR^-/-/ISO CFs exhibited an activated molecular signature enriched in cytokines and growth factors, and their conditioned media induced greater hypertrophy in neonatal cardiomyocytes, revealing a potent paracrine contribution to the remodeling process. These findings demonstrate that the female heart relies on β₂AR signaling to limit acute catecholamine-induced injury, underscoring the potential of β₂AR-targeted interventions as therapeutic strategies in a Takotsubo-like setting.<b>NEW & NOTEWORTHY</b> Takotsubo cardiomyopathy (TTC) disproportionately affects women and is driven by excessive β-adrenergic receptor (βAR) activation. We show that loss of β₂AR signaling exacerbates myocardial injury, creating a proinflammatory and profibrotic milieu that amplifies fibroblast activation and reshapes their paracrine profile. These activated cardiac fibroblasts (CFs) further sustain cardiomyocyte hypertrophy, perpetuating the injury loop in β₂AR-deficient hearts. These findings establish β₂AR as a determinant of cardiac resilience and support β₂AR-directed strategies as interventions in the acute phase of TTC.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C747-C758"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262703","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}