American journal of physiology. Cell physiology最新文献

{"title":"Physical effects of 3-D microenvironments on confined cell behaviors.","authors":"Bao-Qiong Lan, Ya-Jun Wang, Sai-Xi Yu, Wei Liu, Yan-Jun Liu","doi":"10.1152/ajpcell.00288.2024","DOIUrl":"10.1152/ajpcell.00288.2024","url":null,"abstract":"<p><p>Cell migration is a fundamental and functional cellular process, influenced by a complex microenvironment consisting of different cells and extracellular matrix. Recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior. However, due to the complexity of the microenvironment, little is known about how the physical interactions between migrating cells and surrounding microenvironment instructs cell movement. Here, we explore various examples of three-dimensional microenvironment reconstruction models in vitro and describe how the physical interplay between migrating cells and the neighboring microenvironment controls cell behavior. Understanding this mechanical cooperation will provide key insights into organ development, regeneration, and tumor metastasis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1192-C1201"},"PeriodicalIF":5.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153029","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":"Transcriptomic signatures of human single skeletal muscle fibers in response to high-intensity interval exercise.","authors":"Thibaux Van der Stede, Alexia Van de Loock, Eline Lievens, Nurten Yigit, Jasper Anckaert, Ruud Van Thienen, Anneleen Weyns, Pieter Mestdagh, Jo Vandesompele, Wim Derave","doi":"10.1152/ajpcell.00299.2024","DOIUrl":"10.1152/ajpcell.00299.2024","url":null,"abstract":"<p><p>The heterogeneous fiber type composition of skeletal muscle makes it challenging to decipher the molecular signaling events driving the health- and performance benefits of exercise. We developed an optimized workflow for transcriptional profiling of individual human muscle fibers before, immediately after, and after 3 h of recovery from high-intensity interval cycling exercise. From a transcriptional point-of-view, we observe that there is no dichotomy in fiber activation, which could refer to a fiber being recruited or nonrecruited. Rather, the activation pattern displays a continuum with a more uniform response within fast versus slow fibers during the recovery from exercise. The transcriptome-wide response immediately after exercise is characterized by some distinct signatures for slow versus fast fibers, although the most exercise-responsive genes are common between the two fiber types. The temporal transcriptional waves further converge the gene signatures of both fiber types toward a more similar profile during the recovery from exercise. Furthermore, a large heterogeneity among all resting and exercised fibers was observed, with the principal drivers being independent of a slow/fast typology. This profound heterogeneity extends to distinct exercise responses of fibers beyond a classification based on myosin heavy chains. Collectively, our single-fiber methodological approach points to a substantial between-fiber diversity in muscle fiber responses to high-intensity interval exercise.<b>NEW & NOTEWORTHY</b> By development of a single-fiber transcriptomics technology, we assessed the transcriptional events in individual human skeletal muscle fibers upon high-intensity exercise. We demonstrate a large variability in transcriptional activation of fibers, with shared and distinct gene signatures for slow and fast fibers. The heterogeneous fiber-specific exercise response extends beyond this traditional slow/fast categorization. These findings expand on our understanding of exercise responses and uncover a profound between-fiber diversity in muscle fiber activation and transcriptional perturbations.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1249-C1262"},"PeriodicalIF":5.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339325","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":"Asparagine as a signal for glutamine sufficiency via asparagine synthetase: a fresh evidence-based framework in physiology and oncology.","authors":"Babatunde Olawuni, Barrie P Bode","doi":"10.1152/ajpcell.00316.2024","DOIUrl":"10.1152/ajpcell.00316.2024","url":null,"abstract":"<p><p>Among the 20 proteinogenic amino acids, glutamine (GLN) and asparagine (ASN) represent a unique cohort in containing a terminal amide in their side chain, and share a direct metabolic relationship, with glutamine generating asparagine through the ATP-dependent asparagine synthetase (ASNS) reaction. Circulating glutamine levels and metabolic flux through cells and tissues greatly exceed those for asparagine, and \"glutamine addiction\" in cancer has likewise received considerable attention. However, historic and recent evidence collectively suggest that in spite of its modest presence, asparagine plays an outsized regulatory role in cellular function. Here, we present a unifying evidence-based hypothesis that the amides constitute a regulatory signaling circuit, with glutamine as a driver and asparagine as a second messenger that allosterically regulates key biochemical and physiological functions, particularly cell growth and survival. Specifically, it is proposed that ASNS serves as a sensor of substrate sufficiency for S-phase entry and progression in proliferating cells. ASNS-generated asparagine serves as a subsequent second messenger that modulates the activity of key regulatory proteins and promotes survival in the face of cellular stress, and serves as a feed-forward driver of S-phase progression in cell growth. We propose that this signaling pathway be termed the amide signaling circuit (ASC) in homage to the <i>SLC1A5</i>-encoded ASCT2 that transports both glutamine and asparagine in a bidirectional manner, and has been implicated in the pathogenesis of a broad spectrum of human cancers. Support for the ASC model is provided by the recent discovery that glutamine is sensed in primary cilia via ASNS during metabolic stress.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1335-C1346"},"PeriodicalIF":5.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339321","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":"Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.","authors":"Stavroula Tsitkanou, Francielly Morena da Silva, Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Pieter J Koopmans, Sabin Khadgi, Seongkyun Lim, Luca J Delfinis, Tyrone A Washington, Kevin A Murach, Christopher G R Perry, Nicholas P Greene","doi":"10.1152/ajpcell.00497.2024","DOIUrl":"10.1152/ajpcell.00497.2024","url":null,"abstract":"<p><p>Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1 × 10⁶ cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (∼250 nmol/kg body wt/day) and administered to mice beginning 7 days following tumor induction, whereas control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover, and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post hoc test when interactions were significant (<i>P</i> ≤ 0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis, and abated <i>Redd1</i> and <i>Atrogin</i> induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females, SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of <i>Ryr1</i>, <i>Serca1</i>, and <i>Serca2a</i> in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC.<b>NEW & NOTEWORTHY</b> Herein, we assess the efficacy of the mitochondria-targeted antioxidant SkQ1 to mitigate cancer cachexia (CC) in both biological sexes. We demonstrate that SkQ1 administration attenuates muscle wasting induced by C26 tumors in male, but not female, mice. Conversely, we identify that in females, SkQ1 improves muscle contractility. These phenotypic adaptations to SkQ1 are aligned with respective responses in muscle protein synthesis, mitochondrial respiration, and mRNA content of protein turnover, as well as mitochondrial and calcium handling-related markers.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1308-C1322"},"PeriodicalIF":8.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339324","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":"Bacterial lipopolysaccharide inhibits free thiamin uptake along the intestinal tract via interference with membrane expression of thiamin transporters 1 and 2.","authors":"Selvaraj Anthonymuthu, Subrata Sabui, Kameron Isaiah Manzon, Alaullah Sheikh, James M Fleckenstein, Hamid M Said","doi":"10.1152/ajpcell.00570.2024","DOIUrl":"10.1152/ajpcell.00570.2024","url":null,"abstract":"<p><p>This study examined the effect of exposure of small and large intestinal epithelial cells to the bacterial lipopolysaccharide (LPS) on uptake of free form of vitamin B1, i.e., thiamin. The intestinal tract encounters two sources of thiamin: diet and the gut microbiota. Absorption of thiamin in both the small and large intestine occurs via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and -2). Complementary in vitro (human duodenal epithelial HuTu-80 cells and human colonic epithelial NCM460 cells), in vivo (mice), and ex vivo (human primary differentiated enteroid and colonoid monolayers) models were used. The results showed that exposure to LPS causes a significant inhibition in carrier-mediated [³H]-thiamin uptake by small and large intestinal epithelia, with no change in the levels of expression of THTR-1 and -2 mRNAs and their total cellular proteins. However, a significant decrease in the fractions of the THTR-1 and -2 proteins that are expressed at the cell membranes of these epithelial cells was observed. These effects of LPS appeared to involve a protein kinase A (PKA) signaling pathway as activating this pathway caused a reversal in the inhibition of thiamin uptake and level of expression of its transporters at the cell membrane. These findings demonstrate that exposure of gut epithelia to LPS (a situation that occurs under different pathological conditions) leads to inhibition in thiamin uptake due to a decrease in level of expression of its transporters at the cell membrane that is likely mediated via a PKA signaling pathway. <b>NEW & NOTEWORTHY</b> This study shows that the exposure of gut epithelial cells to bacterial LPS negatively impact the uptake process of the free form of vitamin B1 (i.e., thiamin). This appears to be mediated via suppression in the level of thiamin transporters 1 and 2 (THTR-1 and -2) expression at the cell membrane and involves a protein kinase A (PKA) signaling pathway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1163-C1177"},"PeriodicalIF":8.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153026","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":"NF-кB promotes aggresome formation via upregulating HDAC6 and in turn maintaining Vimentin cage.","authors":"Jo-Mei Maureen Chen, Cheng-Yen Chuang, Chiao-Yun Cheng, Yu-Ting Amber Liao, Yi-Hao Calvin Liao, Chih-Ming Pan, Yu-Ting Jenny Huang, Tong-You Wade Wei, Jia-Rong Tsai, Li-Wen Lee, Shao-Chih Chiu, Chang-Tze Ricky Yu","doi":"10.1152/ajpcell.00671.2023","DOIUrl":"10.1152/ajpcell.00671.2023","url":null,"abstract":"<p><p>Proteasome inhibitors have been applied to anticancer therapy by accumulating toxic misfolded proteins. However, chemical inactivation of proteasome generates aggresome, a Vimentin cage-enclosed subcellular structure quarantining HDAC6-Dynein-transported misfolded proteins before the protein toxicants are degraded by autophagy. Hence, aggresome may attenuate proteasome inhibitor drug-induced cytotoxicity. To solve the problem, it is imperative to characterize how cells assemble aggresome. By examining aggresomes in six cell lines, A549 cells were selectively studied for their bigger cell size and moderate aggresome-forming activity. Aggresome grew in size upon continuous exposure of A549 cells to proteasome inhibitor MG132 and reached a mature size around the 16th to 24th hour of treatment. Mechanistic studies revealed that NF-кB translocated to the nucleus in MG132-treated cells, and chemical activation or knockdown of NF-кB enhanced or prohibited aggresome assembly. Further analyses showed that NF-кB upregulated HDAC6, and HDAC6 maintained the Vimentin cage by interacting with Vimentin p72, a key modification of the intermediate filament contributing to aggresome formation. Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.<b>NEW & NOTEWORTHY</b> The study reveals a new mechanism guiding MG132-triggered aggresome formation. NF-кB is quickly activated upon exposure to MG132, and NF-кB upregulates the misfolded protein recognizing factor HDCA6. In addition to collecting misfolded proteins, HDAC6 also binds Vimentin and maintains the Vimentin cage, which quarantines toxic misfolded proteins and protects cells from being toxified by those protein toxicants. Therapeutically, chemical inactivation of NF-кB synergizes MG132-induced cytotoxicity, providing a new strategy to defeat cancers.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1289-C1299"},"PeriodicalIF":5.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387262","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":"Regulation of versican expression in macrophages is mediated by canonical type I interferon signaling via ISGF3.","authors":"Mary Y Chang, Christina K Chan, Jourdan E Brune, Anne M Manicone, Karol Bomsztyk, Charles W Frevert, William A Altemeier","doi":"10.1152/ajpcell.00174.2024","DOIUrl":"10.1152/ajpcell.00174.2024","url":null,"abstract":"<p><p>Growing evidence supports a role for versican as an important component of the inflammatory response, with both pro- and anti-inflammatory roles depending on the specific context of the system or disease under investigation. Our goal is to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. In previous work, we showed that LPS triggers a signaling cascade involving Toll-like receptor (TLR)4, the Trif adaptor, type I interferons, and the type I interferon receptor, leading to increased versican expression by macrophages. In the present study, we used a combination of chromatin immunoprecipitation, siRNA, chemical inhibitors, and mouse model approaches to investigate the regulatory events downstream of the type I interferon receptor to better define the mechanism controlling versican expression. Results indicate that transcriptional regulation by canonical type I interferon signaling via interferon-stimulated gene factor 3 (ISGF3), the heterotrimeric transcription factor complex of Irf9, Stat1, and Stat2, controls versican expression in macrophages exposed to LPS. This pathway is not dependent on MAPK signaling, which has been shown to regulate versican expression in other cell types. The stability of versican mRNA may also contribute to prolonged versican expression in macrophages. These findings strongly support a role for macrophage-derived versican as a type I interferon-stimulated gene and further our understanding of versican's role in regulating inflammation.<b>NEW & NOTEWORTHY</b> We report the novel finding that versican expression is regulated by the interferon-stimulated gene factor 3 (ISGF3) arm of canonical type I Ifn signaling in LPS-stimulated macrophages. This pathway is distinct from mechanisms that control versican expression in other cell types. This suggests that macrophage-derived versican may play a role in limiting a potentially excessive inflammatory response. The detailed understanding of how versican expression is regulated in different cells could lead to unique approaches for enhancing its anti-inflammatory properties.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1274-C1288"},"PeriodicalIF":8.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455988","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 Contribution of the Novel CLTC-VMP1 Fusion Gene to Autophagy Regulation and Energy Metabolism in Cisplatin-Resistant Osteosarcoma.","authors":"Zhiwei Tao, Pingan Zou, Zhengxu Yang, Tao Xiong, Zhi Deng, Qinchan Chen","doi":"10.1152/ajpcell.00302.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00302.2024","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance is a major challenge in the treatment of this disease. This study aims to explore the role of the CLTC-VMP1 gene fusion in the mechanism of chemotherapy resistance in OS and investigate its molecular mechanisms in mediating energy metabolism reprogramming by regulating autophagy and apoptosis balance. Using single-cell transcriptome analysis, the heterogeneity of OS cells and their correlation with resistance to platinum drugs were revealed. Cisplatin-resistant cell lines were established in human OS cell lines for subsequent experiments. Based on transcriptomic analysis, the importance of VMP1 in chemotherapy resistance was confirmed. Lentiviral vectors overexpressing or interfering with VMP1 were used, and it was observed that inhibiting VMP1 could reverse cisplatin resistance, promote cell apoptosis, and inhibit autophagy, as well as mitochondrial respiration and glycolysis. Furthermore, the presence of CLTC-VMP1 gene fusion was validated, and its ability to regulate autophagy and apoptosis balance, promote mitochondrial respiration, and glycolysis was demonstrated. Mouse model experiments further confirmed the promoting effect of CLTC-VMP1 on tumor growth and chemotherapy resistance. In summary, the CLTC-VMP1 gene fusion mediates energy metabolism reprogramming by regulating autophagy and apoptosis balance, which promotes chemotherapy resistance in OS.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492912","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":"ITGA3 participates in the pathogenesis of recurrent spontaneous abortion by downregulating ULK1-mediated autophagy to inhibiting trophoblast function.","authors":"Rui Qi Wang, Fangfang Dai, Zhimin Deng, Lujia Tang, Hua Liu, Liangbin Xia, Yanxiang Cheng","doi":"10.1152/ajpcell.00563.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00563.2024","url":null,"abstract":"<p><p>Recurrent spontaneous abortion (RSA) is a significant challenge encountered by couples of reproductive ages, with inadequate trophoblast invasion identified as a primary factor in RSA pathogenesis. However, the precise molecular mechanisms through which trophoblast cells dysfunction leads to RSA remain incompletely understood. Research has highlighted the critical role of integrins in embryo implantation and development. While integrin α-3 (ITGA3) is recognized for its promotion of invasion in cancer cells, its involvement in miscarriage remains poorly characterized. This investigation initially assessed ITGA3 expression in villous tissues obtained from RSA patients and induced abortion patients. The findings demonstrated a notable reduction in ITGA3 levels in the villous tissues of RSA patients compared control group. Subsequent in vitro analyses indicated that ITGA3 knockdown inhibited the migration, invasion, and proliferation of trophoblast cells. Through RNA sequencing and subsequent experimentation, it was revealed that ITGA3 regulated ULK1-mediated autophagy to influence trophoblast cells invasion, migration, and proliferation. Furthermore, utilizing a miscarriage animal model, the diminished expression of ITGA3 and ULK1 in the placentas of RSA mice was confirmed. In conclusion, the study findings suggest that the downregulation of ITGA3 suppresses ULK1 expression, consequently impeding autophagy to initiation and impeding trophoblast cells invasion and migration, thereby contributing to the pathological progression of RSA.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492908","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":"5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase promotes pulmonary arterial smooth muscle cell proliferation via the Ras signaling pathway.","authors":"Xiaofan Shi, Qian Ma, Yuqing Huo, Yunchao Su","doi":"10.1152/ajpcell.00262.2024","DOIUrl":"10.1152/ajpcell.00262.2024","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of monocrotaline (MCT)-induced PAH rat model, hypoxia-induced PAH mouse model, and platelet-derived growth factor (PDGF)-stimulated PASMCs. Inhibition of ATIC attenuated PDGF-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation, and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Furthermore, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factors MYC, early growth response protein 1 (EGR1), and specificity protein 1 (SP1) directly binds to promoters of <i>Atic</i> gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway.<b>NEW & NOTEWORTHY</b> Our findings highlight the important role of ATIC in the PASMC proliferation of pulmonary vascular remodeling through its modulation of the Ras signaling pathway and its regulation by transcription factors MYC, EGR1, and SP1. ATIC's modulation of Ras signal pathway represents a novel mechanism contributing to PAH development.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C901-C912"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915823","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}