American journal of physiology. Cell physiology最新文献

{"title":"Mechanistic insights into SENP1 and OCT4 interaction in promoting drug resistance and stem cell features in colon cancer.","authors":"Jun Zou, Jing Chen, Lei Deng, Bangran Xu, Tenghua Yu, Jun Wang, Chongwu He","doi":"10.1152/ajpcell.00817.2024","DOIUrl":"10.1152/ajpcell.00817.2024","url":null,"abstract":"<p><p>This study explores the molecular mechanism by which sentrin/SUMO-specific protease 1 (SENP1) promotes cisplatin (Cis) resistance and tumor stem cell characteristics in colon adenocarcinoma (COAD) through deSUMOylation-mediated modification of octamer-binding transcription factor 4 (OCT4). By analyzing single-cell and transcriptome sequencing datasets, we identified key genes and regulatory pathways in both resistant and sensitive COAD cells. Malignant cells were isolated and evaluated for stemness using the infercnv package, and differential genes between Cis-resistant and -sensitive groups were identified. Machine learning algorithms highlighted essential genes, and databases predicted interaction sites between OCT4 and SENP1. In vitro experiments using enriched HCT116 stem cells revealed that SENP1 and OCT4 expression significantly elevated CD44 and CD133 levels, enhancing stemness. Functional assays showed that SENP1's deSUMOylation of OCT4 intensified Cis resistance, migration, and invasion in cisplatin-resistant cell line 116 (Cis-116) cells. In vivo, SENP1 knockdown reduced tumor growth and stem cell markers, whereas OCT4 overexpression escalated tumor metastasis and structural damage. These findings demonstrate that SENP1's modulation of OCT4 is central to COAD's resistance and stem cell properties, offering a novel target for COAD therapy.<b>NEW & NOTEWORTHY</b> This study uncovers the critical role of SENP1 in regulating OCT4 through deSUMOylation, driving Cis resistance and tumor stemness in COAD. Targeting this pathway may provide novel therapeutic strategies for COAD management.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1260-C1278"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595818","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":"GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes.","authors":"Rebecca J Noort, Wesam Salman, Camila Fuchs, Ursula Braun, David Pace, Kathleen A Hodgkinson, Jessica L Esseltine","doi":"10.1152/ajpcell.01025.2024","DOIUrl":"10.1152/ajpcell.01025.2024","url":null,"abstract":"<p><p>Arrhythmogenic cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium, leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, \"The Newfoundland Curse\". ACM in NL is often caused by a fully penetrant heterozygous missense pathogenic variant in the <i>TMEM43</i> gene (<i>TMEM43</i> c.1073C>T; TMEM43 p.S358L). Although the causative variant has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than in females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from two severely affected male Newfoundland patients with ACM (TMEM43 p.S358L). CRISPR-Cas9 was used to genetically \"repair\" the heterozygous TMEM43 variant in ACM patient iPSCs. ACM patient iPSC-cardiomyocytes (iPSC-CMs) with the TMEM43 p.S358L variant display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. GSK3 inhibition significantly increased the protein expression of β-catenin as well as Lamin A/C and ameliorated the proarrhythmic tendencies of ACM patient iPSC-CMs.<b>NEW & NOTEWORTHY</b> This is the first characterization of induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) from Newfoundland patients with ACM. We find that ACM iPSC-CMs exhibit extreme proarrhythmic tendencies that can be normalized with GSK3 inhibition. Importantly, GSK3 inhibition is accompanied by a significant increase in key proteins, such as β-catenin and Lamin A/C, pointing toward a possible mechanism both for disease pathogenesis and therapy via GSK3 inhibitors.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1206-C1219"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584300","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":"Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.","authors":"Joachim Nielsen, Kristine Grøsfjeld Petersen, Martin Eisemann de Almeida, Sam O Shepherd, Britt Christensen, Maria Houborg Petersen, Kurt Højlund, Niels Ørtenblad, Kasper Degn Gejl","doi":"10.1152/ajpcell.00123.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00123.2025","url":null,"abstract":"<p><p>Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared to recreationally active individuals, along with greater whole-body oxygen uptake and maximal fat oxidation rates. In this study, we investigated if these differences manifest in a greater LD-mitochondria contact and how this may relate to the organelles' size, shape, and numerical densities. We obtained skeletal muscle biopsies from 17 male elite triathletes and road cyclists and 7 recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had 2-3-fold greater LD-mitochondria total contact length than the recreationally active individuals. This was related to higher numerical densities of both mitochondria (+30%) and LDs (+100%) in the intermyofibrillar space. Adding data from untrained individuals with equally high intermyofibrillar LD density as the endurance athletes revealed a 24% greater total LD-mitochondria contact length in the endurance athletes. We observed small trivial differences in shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape than small mitochondrial profiles, while large LD profiles were more circular and less irregular than small LD profiles. Within athletes, large intermyofibrillar LD profiles correlated (r=0.72) with a high fraction of PLIN5-positive LDs and their maximal fat oxidation rate was positively associated with an interaction between the profile size of both intermyofibrillar LDs and mitochondria. In conclusion, male endurance athletes have a greater LD-mitochondria contact than recreationally active and untrained individuals. This muscular phenotype is restricted to the intermyofibrillar space and to fibers rich in mitochondria.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656109","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":"Cellular mechanisms underlying overreaching in skeletal muscle following excessive high-intensity interval training.","authors":"Daiki Watanabe, Masanobu Wada","doi":"10.1152/ajpcell.00623.2024","DOIUrl":"10.1152/ajpcell.00623.2024","url":null,"abstract":"<p><p>Overreaching (OR) can be defined as a decline in physical performance resulting from excessive exercise training, necessitating days to weeks recovery. Impairments in the contractile function of skeletal muscle are believed to be a primary factor contributing to OR. However, the cellular mechanism triggering OR remains unclear. The purpose of this study was to elucidate the mechanisms underlying OR. Rats' plantar flexor muscles were subjected to repeated electrical stimulations mimicking excessive high-intensity interval training (HIIT) daily for 13 consecutive days, and isometric torques were monitored. The torque was measured one day after HIIT, and subsequently, the physiological function of type II fibers was analyzed by using mechanically skinned-fiber technique. Eleven of 17 rats exhibited torque decline, whereas others did not. Thus, the rats were divided into OR and nonoverreaching (NOR) groups. Skinned fibers from the gastrocnemius (GAS) muscles of both groups showed decreased depolarization-induced force and increased myofibrillar Ca²⁺ sensitivity. However, the fibers from the OR group, but not the NOR group, exhibited a decrease in myofibrillar maximal force. Biochemical analyses of a superficial region of GAS muscle revealed that α-actinin 2 content was increased in the NOR group, but not in the OR group, whereas calpain-3 autolysis was increased in the OR group, but not in the NOR group. These findings shed light on the cellular mechanism underlying OR: OR following excessive HIIT was induced by a decreased myofibrillar maximal force, whereas Ca²⁺ sensitivity was increased.<b>NEW & NOTEWORTHY</b> An early sign of overtraining is a performance impairment known as overreaching (OR). This study revealed the cellular mechanism underlying OR by combining in vivo fatiguing contractions with mechanically skinned-fiber technique. Thirteen consecutive days of intense training result in myofibrillar force depression in OR. This study provides valuable insights not only for athletes and coaches but also for nonathletes who incorporate exercise into their daily activity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C921-C938"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187660","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":"Transmission of peripheral blood α-synuclein fibrils exacerbates synucleinopathy and neurodegeneration in Parkinson's disease by endothelial Lag3 endocytosis.","authors":"Qingrui Duan, Qingxi Zhang, ShuoLin Jiang, Kun Nie, Shujun Feng, Yihui Qiu, Peikun He, Yuxuan Xing, Jiaxuan Liu, Guixian Ma, Yuhu Zhang, Yuyuan Gao, Lijuan Wang","doi":"10.1152/ajpcell.00639.2024","DOIUrl":"10.1152/ajpcell.00639.2024","url":null,"abstract":"<p><p>Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal α-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFFs) can be detected in the serum of patients with PD. The peripheral blood α-syn PFF can cross the blood-brain barrier (BBB) and aggravate neuronal damage, but the mechanism remains to be elucidated. We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T + Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation, and pathologic α-syn deposition in A53T ONLY, but not in A53T + Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. Our findings reveal the role of peripheral blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD.<b>NEW & NOTEWORTHY</b> This study highlights the transmission mechanism of peripheral blood α-synuclein preformed fibrils (α-syn PFFs) through endothelial Lag3 endocytosis in the mild pathology or early-stage Parkinson's disease (PD). Targeting endothelial Lag3 as a perspective of decreasing peripheral blood α-syn PFFs transmission may be a disease-modifying therapy in early-stage PD.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C836-C855"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798696","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":"Body composition alterations in patients with lung cancer.","authors":"Deena B Snoke, Gary S Atwood, Emma R Bellefleur, Alice M Stokes, Michael J Toth","doi":"10.1152/ajpcell.01048.2024","DOIUrl":"10.1152/ajpcell.01048.2024","url":null,"abstract":"<p><p>Most patients with lung cancer experience cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting. Knowledge of body composition changes in patients is limited, however, because most studies have been cross-sectional, comparing patients with noncancer controls or patients with and without CC. Few studies, in contrast, have evaluated body composition in patients with lung cancer over time. This review examines our current understanding of longitudinal body composition changes in patients with lung cancer and identifies modifying factors contributing to variation in muscle and adipose tissue wasting, focusing on biological sex. We identified 32 studies conducting longitudinal measurements of body composition by computed tomography, bioelectrical impedance, dual X-ray absorptiometry, or total body nitrogen, with a total of <i>n</i> = 3,951 patients (35% female). All studies evaluated changes following diagnosis while patients were receiving treatment. Most studies reporting muscle-specific outcomes show decreased skeletal muscle mass, with more pronounced muscle wasting in males and male-enriched populations. In a small number of studies reporting muscle density, the majority show increased myosteatosis. Adiposity changes are less frequently reported, although wasting appears more prevalent in late-stage disease. Further studies are needed to define adipose changes along the lung cancer continuum. Our review emphasizes the need for balanced recruitment based on biological sex and sex-based analyses. In addition, consensus reporting of relevant patient data and outcomes in future studies will allow for meta-analysis and assist in the development of effective treatments for lung CC.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C872-C886"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062983","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":"Corrigendum for Watso et al., volume 327, 2024, p. C446-C461.","authors":"","doi":"10.1152/ajpcell.00694.2024_COR","DOIUrl":"10.1152/ajpcell.00694.2024_COR","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 3","pages":"C1090"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565778","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":"<i>O-</i>GlcNAcylation regulates tyrosine hydroxylase serine 40 phosphorylation and l-DOPA levels.","authors":"Bruno da Costa Rodrigues, Miguel Clodomiro Dos Santos Lucena, Anna Carolina Rego Costa, Isadora de Araújo Oliveira, Mariana Thaumaturgo, Yolanda Paes-Colli, Danielle Beckman, Sergio T Ferreira, Fernando Garcia de Mello, Ricardo Augusto de Melo Reis, Adriane Regina Todeschini, Wagner Barbosa Dias","doi":"10.1152/ajpcell.00215.2024","DOIUrl":"10.1152/ajpcell.00215.2024","url":null,"abstract":"<p><p>β-<i>O-</i>linked-<i>N</i>-acetylglucosamine (<i>O-</i>GlcNAcylation) is a post-translational modification (PTM) characterized by the covalent attachment of a single moiety of <i>N</i>-acetylglucosamine (GlcNAc) on serine/threonine residues in proteins. Tyrosine hydroxylase (TH), the rate-limiting step enzyme in the catecholamine synthesis pathway and responsible for the production of the dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), has its activity regulated by phosphorylation. Here, we show an inverse feedback mechanism between <i>O-</i>GlcNAcylation and phosphorylation of TH at serine 40 (TH pSer40). First, we showed that, during PC12 cells neuritogenesis, TH <i>O-</i>GlcNAcylation decreases concurrently with the increase of pSer40. In addition, an increase in <i>O-</i>GlcNAcylation induces a decrease in TH pSer40 only in undifferentiated PC12 cells, whereas the decrease in <i>O-</i>GlcNAcylation leads to an increase in TH pSer40 levels in both undifferentiated and differentiated PC12 cells. We further show that this feedback culminates on the regulation of l-DOPA intracellular levels. Interestingly, it is noteworthy that decreasing <i>O-</i>GlcNAcylation is much more effective on TH pSer40 regulation than increasing its levels. Finally, ex vivo analysis confirmed the upregulation of TH pSer40 when <i>O-</i>GlcNAcylation levels are reduced in dopaminergic neurons from C57Bl/6 mice. Taken together, these findings demonstrate a dynamic control of l-DOPA production by a molecular cross talk between <i>O-</i>GlcNAcylation and phosphorylation at Ser40 in TH.<b>NEW & NOTEWORTHY</b> This study shows how β-<i>O-</i>linked-<i>N</i>-acetylglucosamine (<i>O-</i>GlcNAcylation) modulates tyrosine hydroxylase (TH) activity, revealing a negative feedback loop with Ser40 phosphorylation both in vitro and ex vivo, which directly influences on l-3,4-dihydroxyphenylalanine (l-DOPA) production. These findings offer insights into neurotransmitter homeostasis regulation, with implications for understanding and potentially treating disorders linked to aberrant catecholamine signaling.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C825-C835"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051240","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":"Activated cardiac fibroblasts are a primary source of high-molecular-weight hyaluronan production.","authors":"Danielle T Little, Caitlin M Howard, Emma Pendergraft, Kenneth R Brittian, Timothy N Audam, Exile W Lukudu, Juliette Smith, Daniel Nguyen, Yoshihiro Nishida, Yu Yamaguchi, Robert E Brainard, Richa A Singhal, Steven P Jones","doi":"10.1152/ajpcell.00786.2024","DOIUrl":"10.1152/ajpcell.00786.2024","url":null,"abstract":"<p><p>During acute myocardial infarction, the composition of the extracellular matrix changes remarkably. One of the most notable changes in the extracellular matrix is in the accumulation of collagen; however, hyaluronan rivals collagen in its abundance. Yet, the extent to which specific cells and enzymes may contribute to such accumulation has been largely unexplored. Here, we hypothesized that activated cardiac fibroblasts produce hyaluronan via hyaluronan synthase 2 (HAS2). We show that hyaluronan accumulates following myocardial infarction and persists through at least 4 wk. Our analyses of failing heart RNA sequencing data suggest that fibroblasts are the cells most changed in the expression of <i>HAS2</i>. Given these insights, we used HAS2 gain- and loss-of-function approaches to examine the extent to which activated cardiac fibroblasts produce hyaluronan. Transforming growth factor β (TGFβ)-induced activation of fibroblasts caused a significant increase in <i>Has2</i> mRNA and concomitant accumulation of hyaluronan >1 MDa in size. Deletion of <i>Has2</i> abrogated TGFβ-induced production of hyaluronan. In addition, overexpression of <i>Has2</i> was sufficient to cause an increase in hyaluronan accumulation in the absence of TGFβ-induced activation. Our data indicated negligible impacts of <i>Has2</i> on proliferation, migration, and collagen production. Exposing fibroblasts to exogenous hyaluronan also had minimal impact on fibroblasts. We also assessed whether fibroblast-borne <i>Hyal2</i> plays a role in the degradation of hyaluronan, and our data indicated little impact of <i>Hyal2</i> on hyaluronan accumulation (or even any impacts on the transcriptional profile of fibroblasts). Activated fibroblasts produce high-molecular-weight hyaluronan via <i>Has2</i>, which occurs independent of other fibroblast functions.<b>NEW & NOTEWORTHY</b> Activated cardiac fibroblasts produce copious quantities of collagen, and much is known about this process. They also produce hyaluronan, which is abundant in the extracellular matrix, but less is known about hyaluronan. Here, we identify cardiac fibroblasts as major producers of hyaluronan and, specifically, that they produce high-molecular-weight hyaluronan via HAS2. This has important implications for ventricular remodeling and for metabolic regulation of activated fibroblasts, as they produce this abundant matrix component.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C939-C953"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051019","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":"Inhibition of Bif-1 confers cardio-protection in myocardial infarction.","authors":"Yi Xu, Zhirui Zheng, Xin Jiang, Xinqiuyue Wang, Qiuxia Xu, Xianneng Lu, Yipu Huang, Yuan Qin, Ning Hou, Yun Liu","doi":"10.1152/ajpcell.00473.2024","DOIUrl":"10.1152/ajpcell.00473.2024","url":null,"abstract":"<p><p>Myocardial infarction (MI) remains a major cause of chronic heart failure. Endoplasmic reticulum (ER) stress is an emerging therapeutic strategy to prevent adverse remodeling of the infarcted heart. However, little is known about how Bax-interacting protein 1 (Bif-1), a member of the endophilin B family, is involved in mediating cardiac ER stress in ischemic heart disease. Here, a combination of a left anterior descending coronary artery ligation mouse model and an adenovirus-based transfection strategy was used to investigate the effect of Bif-1 on cardiac remodeling and function after MI. 4-Phenylbutyric acid (4-PBA) was used to understand the role of ER stress in cardiac remodeling. To discover the molecular mechanism, an RNA sequencing study was performed. We found that Bif-1 expression was highly elevated in the heart infarct border zone post-MI and neonatal rat cardiomyocytes treated with oxygen and glucose deprivation. Adenovirus-based knockdown of Bif-1 protected the heart from MI as demonstrated by attenuated maladaptive remodeling and preserved contractile function. ER stress inhibition by 4-PBA alleviated the adverse effects of Bif-1 overexpression on cardiac structure and function. Furthermore, we explored the underlying mechanism by RNA sequencing and identified Bif-1 as a molecule involved in cardiac lipid metabolism. In conclusion, our study identifies Bif-1 as a negative regulator of cardiac protection in MI. Inhibition of Bif-1 alleviates ER stress, which may restore lipid metabolism homeostasis to preserve cardiac function post-MI. Therefore, Bif-1 is a potential novel therapeutic target for ischemic heart disease.<b>NEW & NOTEWORTHY</b> Our study demonstrated that Bif-1 contributes to adverse cardiac remodeling and dysfunction following MI by promoting ER stress. Pharmacological inhibition of ER stress ameliorates cardiac remodeling and dysfunction. In addition, we identified Bif-1 as a negative regulator of cardiac lipid metabolism post-MI, as shown by elevated expression of Acox1, Pla2g7, Acsbg1, Acsl5, Ch25h, and Bcat1 in the heart. These findings suggest that Bif-1 plays a crucial role in cardiac decline post-MI.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1076-C1089"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466703","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}