Pub Date : 2024-10-22DOI: 10.1152/ajpcell.00630.2024
Lisa Hahnefeld, Juliane Hackel, Sandra Trautmann, Carlo Angioni, Yannick Schreiber, Robert Gurke, Dominique Thomas, Sabine Wicker, Gerd Geisslinger, Irmgard Tegeder
Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements manifested in plasma lipidomic profiles, obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 years, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, while ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress (PSQ30 questionnaire), which was however, associated with BMI in men, but not in women. None of the lipid species or classes showed a similar "age X sex X BMI" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with BMI and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.
感知压力被认为是代谢、血管、精神和免疫疾病的发病机制之一,而女性和男性的易感性有所不同。本研究调查了感知到的压力和/或人口统计学变量(包括性别、年龄、体重指数、经常服用的处方药、偶尔服用的镇痛药或膳食补充剂)是否以及如何体现在通过靶向和非靶向质谱分析获得的血浆脂质体图谱中。研究对象包括 217 名健康女性和 108 名健康男性,年龄在 18-68 岁之间,男女比例为 2:1,以考虑到使用/未使用避孕药具的女性。不出所料,男性的硫酸脱氢表雄酮(DHEAS)和神经酰胺含量均高于女性,而且随着年龄的增长,DHEAS有所下降,而神经酰胺则有所增加。与预期相反,DHEAS 和神经酰胺均与压力感知(PSQ30 问卷)无关,但男性的压力感知与体重指数有关,而女性则与之无关。没有一种脂质或脂质类别显示出类似的 "年龄 X 性别 X BMI "相互作用,但内源性大麻素棕榈酰乙醇酰胺(PEA)与 BMI 和高血压相关。与感知压力无关,女性的溶血磷脂酰胆碱(LPCs)低于男性,而女性的 LPC 代谢物溶血磷脂酸(LPAs)高于男性。使用口服避孕药的女性体内 LPA 与 LPC 的比率特别高,这表明 LPCs 在细胞外转化为 LPAs 的过程中受到了激素的强烈诱导,而这种转化是由磷脂酶 D 和自体脂酶催化的。研究结果表明,在感知压力和脂质组学特征方面存在复杂的性别差异,使用避孕药会加剧后者,但感知压力和脂质并不直接相关。
{"title":"Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress.","authors":"Lisa Hahnefeld, Juliane Hackel, Sandra Trautmann, Carlo Angioni, Yannick Schreiber, Robert Gurke, Dominique Thomas, Sabine Wicker, Gerd Geisslinger, Irmgard Tegeder","doi":"10.1152/ajpcell.00630.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00630.2024","url":null,"abstract":"<p><p>Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements manifested in plasma lipidomic profiles, obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 years, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, while ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress (PSQ30 questionnaire), which was however, associated with BMI in men, but not in women. None of the lipid species or classes showed a similar \"age X sex X BMI\" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with BMI and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492906","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}
Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The crosstalk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were utilized to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. Additionally, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE.
{"title":"TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy.","authors":"Yijia Lin, Lizhen Cheng, Yixin Chen, Wei Li, Qihao Guo, Ya Miao","doi":"10.1152/ajpcell.00322.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00322.2024","url":null,"abstract":"<p><p>Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The crosstalk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were utilized to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. Additionally, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492911","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}
Pub Date : 2024-10-14DOI: 10.1152/ajpcell.00484.2024
Kalidas Ramamoorthy, Subrata Sabui, George Kim, James M Fleckenstein, Alaullah Sheikh, Hamid M Said
The human colonic thiamin pyrophosphate transporter (hcTPPT) mediates the uptake of the microbiota-generated and phosphorylated form of vitamin B1 (i. e., thiamin pyrophosphate) in the large intestine. Expression of hcTPPT along the absorptive tract is restricted to the large intestine and the transporter is exclusively localized at the apical membrane domain of the polarized epithelial cells/colonocytes. Previous studies have characterized different physiological/pathophysiological aspects of the hcTPPT system, but nothing is currently known on whether the transporter has interacting partner(s) that affects its physiology/biology. We addressed this issue using a Y2H to screen a human colonic cDNA library, and have identified 3 putative interactors, namely IQGAP-2, SNX-6 and DMXL-1. Focusing on IQGAP-2 (whose expression in human colonocytes is the highest), we found (using fluorescent microscopy imaging and co-immunoprecipitation approaches) the putative interactor to co-localize with hcTPPT, and to directly interact with the transporter. Also, over-expressing IQGAP-2 in NCM460 cells and in human primary differentiated colonoid monolayers was found to lead to significant (P < 0.01) induction in TPP uptake, while it's knocking down (using gene-specific siRNAs) caused significant (P < 0.01 & < 0.05) decrease in uptake. Furthermore, over-expressing IQGAP-2 in NCM460 cells was found to lead to a significant enhancement in hcTPPT protein stability. Finally, we found the expression of IQGAP-2 to be markedly suppressed in conditions/factors that negatively impact colonic TPP uptake. These results identify the IQGAP-2 as an interacting partner with the hcTPPT in human colonocytes and show that this interaction has physiological and biological consequences.
{"title":"IQGAP-2: A novel interacting partner for the Human Colonic Thiamin Pyrophosphate Transporter (hcTPPT).","authors":"Kalidas Ramamoorthy, Subrata Sabui, George Kim, James M Fleckenstein, Alaullah Sheikh, Hamid M Said","doi":"10.1152/ajpcell.00484.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00484.2024","url":null,"abstract":"<p><p>The human colonic thiamin pyrophosphate transporter (hcTPPT) mediates the uptake of the microbiota-generated and phosphorylated form of vitamin B1 (i. e., thiamin pyrophosphate) in the large intestine. Expression of hcTPPT along the absorptive tract is restricted to the large intestine and the transporter is exclusively localized at the apical membrane domain of the polarized epithelial cells/colonocytes. Previous studies have characterized different physiological/pathophysiological aspects of the hcTPPT system, but nothing is currently known on whether the transporter has interacting partner(s) that affects its physiology/biology. We addressed this issue using a Y2H to screen a human colonic cDNA library, and have identified 3 putative interactors, namely IQGAP-2, SNX-6 and DMXL-1. Focusing on IQGAP-2 (whose expression in human colonocytes is the highest), we found (using fluorescent microscopy imaging and co-immunoprecipitation approaches) the putative interactor to co-localize with hcTPPT, and to directly interact with the transporter. Also, over-expressing IQGAP-2 in NCM460 cells and in human primary differentiated colonoid monolayers was found to lead to significant (<i>P <</i> 0.01) induction in TPP uptake, while it's knocking down (using gene-specific siRNAs) caused significant (<i>P</i> < 0.01 & <i><</i> 0.05) decrease in uptake. Furthermore, over-expressing IQGAP-2 in NCM460 cells was found to lead to a significant enhancement in hcTPPT protein stability. Finally, we found the expression of IQGAP-2 to be markedly suppressed in conditions/factors that negatively impact colonic TPP uptake. These results identify the IQGAP-2 as an interacting partner with the hcTPPT in human colonocytes and show that this interaction has physiological and biological consequences.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455987","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}
Pub Date : 2024-10-14DOI: 10.1152/ajpcell.00241.2024
Kellina Maduray, Jingquan Zhong
Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition within the myocardium, poses a significant challenge in cardiovascular health, contributing to various cardiac pathologies. Ketone bodies (KBs), particularly β-hydroxybutyrate (β-OHB), have emerged as subjects of interest due to their potential cardioprotective effects. However, their specific influence on cardiac fibrosis remains underexplored. This literature review comprehensively examines the relationship between KBs and cardiac fibrosis, elucidating potential mechanisms through which KBs modulate fibrotic pathways. A multifaceted interplay exists between KBs and key mediators of cardiac fibrosis. While some studies indicate a pro-fibrotic role for KBs, others highlight their potential to attenuate fibrosis and cardiac remodeling. Mechanistically, KBs may regulate fibrotic pathways through modulation of cellular components such as cardiac fibroblasts, macrophages, and lymphocytes, as well as extracellular matrix proteins. Furthermore, the impact of KBs on cellular processes implicated in fibrosis, including oxidative stress, chemokine and cytokine expression, caspase activation, and inflammasome signaling are explored. While conflicting findings exist regarding the effects of KBs on these processes, emerging evidence suggests a predominantly beneficial role in mitigating inflammation and oxidative stress associated with fibrotic remodeling. Overall, this review underscores the importance of elucidating the complex interplay between KB metabolism and cardiac fibrosis. Insights gained have the potential to inform novel therapeutic strategies for managing cardiac fibrosis and associated cardiovascular disorders, highlighting the need for further research in this area.
心肌纤维化的特点是细胞外基质(ECM)在心肌内过度沉积,它对心血管健康构成了重大挑战,并导致各种心脏病变。酮体(KBs),尤其是β-羟基丁酸(β-OHB),因其潜在的心脏保护作用而成为人们关注的对象。然而,它们对心脏纤维化的具体影响仍未得到充分探讨。这篇文献综述全面研究了KBs与心脏纤维化之间的关系,阐明了KBs调节纤维化途径的潜在机制。KBs与心脏纤维化的关键介质之间存在着多方面的相互作用。一些研究表明,KBs 具有促进纤维化的作用,而另一些研究则强调了其减轻纤维化和心脏重塑的潜力。从机理上讲,KBs 可通过调节心脏成纤维细胞、巨噬细胞和淋巴细胞等细胞成分以及细胞外基质蛋白来调节纤维化途径。此外,还探讨了 KBs 对与纤维化有关的细胞过程的影响,包括氧化应激、趋化因子和细胞因子表达、Caspase 激活和炎性体信号转导。虽然关于 KBs 对这些过程的影响存在相互矛盾的研究结果,但新出现的证据表明,KBs 在减轻与纤维化重塑相关的炎症和氧化应激方面起着主要的有益作用。总之,本综述强调了阐明 KB 代谢与心脏纤维化之间复杂的相互作用的重要性。所获得的见解有可能为管理心肌纤维化和相关心血管疾病的新型治疗策略提供依据,并强调了在这一领域开展进一步研究的必要性。
{"title":"Emerging Roles of Ketone Bodies in Cardiac Fibrosis.","authors":"Kellina Maduray, Jingquan Zhong","doi":"10.1152/ajpcell.00241.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00241.2024","url":null,"abstract":"<p><p>Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition within the myocardium, poses a significant challenge in cardiovascular health, contributing to various cardiac pathologies. Ketone bodies (KBs), particularly β-hydroxybutyrate (β-OHB), have emerged as subjects of interest due to their potential cardioprotective effects. However, their specific influence on cardiac fibrosis remains underexplored. This literature review comprehensively examines the relationship between KBs and cardiac fibrosis, elucidating potential mechanisms through which KBs modulate fibrotic pathways. A multifaceted interplay exists between KBs and key mediators of cardiac fibrosis. While some studies indicate a pro-fibrotic role for KBs, others highlight their potential to attenuate fibrosis and cardiac remodeling. Mechanistically, KBs may regulate fibrotic pathways through modulation of cellular components such as cardiac fibroblasts, macrophages, and lymphocytes, as well as extracellular matrix proteins. Furthermore, the impact of KBs on cellular processes implicated in fibrosis, including oxidative stress, chemokine and cytokine expression, caspase activation, and inflammasome signaling are explored. While conflicting findings exist regarding the effects of KBs on these processes, emerging evidence suggests a predominantly beneficial role in mitigating inflammation and oxidative stress associated with fibrotic remodeling. Overall, this review underscores the importance of elucidating the complex interplay between KB metabolism and cardiac fibrosis. Insights gained have the potential to inform novel therapeutic strategies for managing cardiac fibrosis and associated cardiovascular disorders, highlighting the need for further research in this area.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455973","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}
Pub Date : 2024-10-07DOI: 10.1152/ajpcell.00347.2024
Christopher Lee, Philip C Woods, Amanda E Paluch, Mark S Miller
Human studies examining the cellular mechanisms behind sarcopenia, or age-related loss of skeletal muscle mass and function, have produced inconsistent results. A systematic review and meta-analysis were performed to determine the aging effects on protein expression, size and distribution of fibers with various myosin heavy chain (MyHC) isoforms. Study eligibility included MyHC comparisons between young (18-49 years) and older (≥ 60 years) adults, with 27 studies identified. Relative protein expression was higher with age for the slow-contracting MyHC I fibers, with correspondingly lower fast-contracting MyHC II and IIA values. Fiber sizes were similar with age for MyHC I, while smaller for MyHC II and IIA. Fiber distributions were similar with age. When separated by sex, the few studies that examined females showed atrophy of MyHC II and IIA fibers with age, but no change in MyHC protein expression. Additional analyses by measurement technique, physical activity, and muscle biopsied provided important insights. In summary, age-related atrophy in fast-contracting fibers lead to more of the slow-contracting, lower force-producing isoform in older male muscles, which helps explain their age-related loss in whole muscle force, velocity, and power. Exercise or pharmacological interventions that shift MyHC expression towards faster isoforms and/or increase fast-contracting fiber size should decrease the prevalence of sarcopenia. Our findings also indicate that future studies need to include or focus solely on females, measure MyHC IIA and IIX isoforms separately, examine fiber type distribution, sample additional muscles to the vastus lateralis, and incorporate an objective measurement of physical activity.
人类对肌肉疏松症(与年龄有关的骨骼肌质量和功能丧失)背后的细胞机制进行了研究,但结果并不一致。为了确定衰老对各种肌球蛋白重链(MyHC)异构体的蛋白质表达、大小和纤维分布的影响,我们进行了系统回顾和荟萃分析。研究资格包括对年轻人(18-49 岁)和老年人(≥ 60 岁)的 MyHC 进行比较,共确定了 27 项研究。随着年龄的增长,慢收缩 MyHC I 纤维的相对蛋白表达量较高,相应地,快收缩 MyHC II 和 IIA 值较低。随着年龄的增长,MyHC I 纤维的大小相似,而 MyHC II 和 IIA 纤维的大小较小。纤维分布与年龄相似。如果按性别区分,少数研究显示女性的肌强直素 II 和 IIA 纤维随着年龄的增长而萎缩,但肌强直素蛋白的表达没有变化。按测量技术、体力活动和肌肉活检进行的其他分析提供了重要的见解。总之,在老年男性肌肉中,与年龄相关的快速收缩纤维萎缩导致了更多的慢速收缩、低力异构体,这有助于解释与年龄相关的整块肌肉力、速度和力量的损失。通过运动或药物干预,将 MyHC 的表达转向较快的同工酶和/或增加快速收缩纤维的大小,应能降低肌肉疏松症的发病率。我们的研究结果还表明,未来的研究需要包括女性或仅关注女性,分别测量 MyHC IIA 和 IIX 同工酶,检查纤维类型分布,对阔筋膜外的其他肌肉进行抽样调查,并纳入体育锻炼的客观测量方法。
{"title":"Effects of age on human skeletal muscle: A systematic review and meta-analysis of myosin heavy chain isoform protein expression, fiber size and distribution.","authors":"Christopher Lee, Philip C Woods, Amanda E Paluch, Mark S Miller","doi":"10.1152/ajpcell.00347.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00347.2024","url":null,"abstract":"<p><p>Human studies examining the cellular mechanisms behind sarcopenia, or age-related loss of skeletal muscle mass and function, have produced inconsistent results. A systematic review and meta-analysis were performed to determine the aging effects on protein expression, size and distribution of fibers with various myosin heavy chain (MyHC) isoforms. Study eligibility included MyHC comparisons between young (18-49 years) and older (≥ 60 years) adults, with 27 studies identified. Relative protein expression was higher with age for the slow-contracting MyHC I fibers, with correspondingly lower fast-contracting MyHC II and IIA values. Fiber sizes were similar with age for MyHC I, while smaller for MyHC II and IIA. Fiber distributions were similar with age. When separated by sex, the few studies that examined females showed atrophy of MyHC II and IIA fibers with age, but no change in MyHC protein expression. Additional analyses by measurement technique, physical activity, and muscle biopsied provided important insights. In summary, age-related atrophy in fast-contracting fibers lead to more of the slow-contracting, lower force-producing isoform in older male muscles, which helps explain their age-related loss in whole muscle force, velocity, and power. Exercise or pharmacological interventions that shift MyHC expression towards faster isoforms and/or increase fast-contracting fiber size should decrease the prevalence of sarcopenia. Our findings also indicate that future studies need to include or focus solely on females, measure MyHC IIA and IIX isoforms separately, examine fiber type distribution, sample additional muscles to the vastus lateralis, and incorporate an objective measurement of physical activity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387260","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}
Pub Date : 2024-10-01Epub Date: 2024-08-12DOI: 10.1152/ajpcell.00262.2024
Xiaofan Shi, Qian Ma, Yuqing Huo, Yunchao Su
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 Atic 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.NEW & NOTEWORTHY 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.
{"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":null,"pages":null},"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}
Pub Date : 2024-10-01Epub Date: 2024-08-19DOI: 10.1152/ajpcell.00049.2024
André L L Monteiro, Marcos Eliezeck, Sérgio R A Scalzo, Mário Morais Silva, Bruno Sanches, Katyana K S Ferreira, Maristela O Poletini, Rodrigo A Peliciari-Garcia, Stêfany B A Cau, Robson A Souza Santos, Silvia Guatimosim
The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. β-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. NG-nitro-l-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling.NEW & NOTEWORTHY Alamandine, a member of the renin-angiotensin system, serves critical roles in cardioprotection, including the modulation of cardiomyocyte contractility. Whether this effect varies along the day is unknown. Our results provide evidence that alamandine via receptor MrgD exerts opposing actions on cardiomyocyte shortening, enhancing, or reducing contraction depending on the time of day. These findings may have significant implications for the development and effectiveness of future cardiac therapies.
肾素-血管紧张素系统(RAS)由一系列肽、受体和酶组成,在维持心血管平衡方面发挥着关键作用。该系统中最重要的角色是血管紧张素-II 和血管紧张素-(1-7)肽。我们的研究小组最近证明,阿拉曼丁(ALA)是一种在结构和功能上与血管紧张素-(1-7)相似的多肽,它能与心肌细胞相互作用,通过与 Mas 相关的 G 蛋白偶联受体成员 D(MrgD)增强收缩力。目前还不清楚这种调节作用是否会随着一天中不同阶段的变化而变化。为了解决这个问题,我们评估了 ALA 诱导的小鼠心肌细胞在四个 Zeitgeber 时间(ZTs)的收缩力反应。在 ZT2(光照阶段),ALA 以依赖于 MrgD 受体的方式增强了心肌细胞的缩短,这与 NO 的产生有关。在 ZT14(暗期),ALA 对心肌细胞收缩产生负向调节。MrgD激动剂β-丙氨酸再现了ALA对心肌细胞缩短的时间效应。氮氧化物合成酶抑制剂 L-NG-硝基精氨酸甲酯(L-NAME)阻断了 ALA 在 ZT2 诱导的缩短率增加。在 ZT 8 和 20 时,未观察到 ALA 对肌细胞缩短的影响。我们的研究结果表明,心肌细胞中的 ALA/MrgD 信号传导受时间调节。这一发现对结合时间疗法的药理方法具有重要意义,可治疗昼夜节律紊乱和激素信号转导引发的心脏疾病。
{"title":"Time of day affects MrgD-dependent modulation of cardiomyocyte contractility.","authors":"André L L Monteiro, Marcos Eliezeck, Sérgio R A Scalzo, Mário Morais Silva, Bruno Sanches, Katyana K S Ferreira, Maristela O Poletini, Rodrigo A Peliciari-Garcia, Stêfany B A Cau, Robson A Souza Santos, Silvia Guatimosim","doi":"10.1152/ajpcell.00049.2024","DOIUrl":"10.1152/ajpcell.00049.2024","url":null,"abstract":"<p><p>The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. β-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. <i>N</i><sup>G</sup>-nitro-l-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling.<b>NEW & NOTEWORTHY</b> Alamandine, a member of the renin-angiotensin system, serves critical roles in cardioprotection, including the modulation of cardiomyocyte contractility. Whether this effect varies along the day is unknown. Our results provide evidence that alamandine via receptor MrgD exerts opposing actions on cardiomyocyte shortening, enhancing, or reducing contraction depending on the time of day. These findings may have significant implications for the development and effectiveness of future cardiac therapies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003396","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}
Pub Date : 2024-10-01Epub Date: 2024-08-26DOI: 10.1152/ajpcell.00367.2024
Lei Lei, Ting Zhu, Tian-Jiao Cui, Yvonne Liu, Johann-Georg Hocher, Xin Chen, Xue-Mei Zhang, Kai-Wen Cai, Zi-Yan Deng, Xiao-Hua Wang, Chun Tang, Lian Lin, Christoph Reichetzeder, Zhi-Hua Zheng, Berthold Hocher, Yong-Ping Lu
The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose cotransporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in individuals with obesity and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared with NCD mice (all P < 0.05). EMPA treatment significantly alleviated these parameters (all P < 0.05). Multitissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of Firmicutes and Desulfovibrio and increased abundance of Akkermansia (all P < 0.05). The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG. NEW & NOTEWORTHY Our study uncovered that empagliflozin (EMPA) potentially protects renal function and morphology in obesity-related glomerulopathy (ORG) mice by regulating the gut-kidney axis. EMPA's reno-protective effects in ORG mice are associated with the lipid metabolism, especially in glycerophospholipid metabolism and the pantothenate/CoA synthesis pathways. EMPA's modulation of gut microbiota appears to be pivotal in suppressing glycerol 3-phosphate and CoA synthesis. The insights into gut microbiota-host metabolic interactions offer a novel therapeutic approach for ORG.
{"title":"Renoprotective effects of empagliflozin in high-fat diet-induced obesity-related glomerulopathy by regulation of gut-kidney axis.","authors":"Lei Lei, Ting Zhu, Tian-Jiao Cui, Yvonne Liu, Johann-Georg Hocher, Xin Chen, Xue-Mei Zhang, Kai-Wen Cai, Zi-Yan Deng, Xiao-Hua Wang, Chun Tang, Lian Lin, Christoph Reichetzeder, Zhi-Hua Zheng, Berthold Hocher, Yong-Ping Lu","doi":"10.1152/ajpcell.00367.2024","DOIUrl":"10.1152/ajpcell.00367.2024","url":null,"abstract":"<p><p>The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose cotransporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in individuals with obesity and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared with NCD mice (all <i>P</i> < 0.05). EMPA treatment significantly alleviated these parameters (all <i>P</i> < 0.05). Multitissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of <i>Firmicutes</i> and <i>Desulfovibrio</i> and increased abundance of <i>Akkermansia</i> (all <i>P</i> < 0.05). The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG. <b>NEW & NOTEWORTHY</b> Our study uncovered that empagliflozin (EMPA) potentially protects renal function and morphology in obesity-related glomerulopathy (ORG) mice by regulating the gut-kidney axis. EMPA's reno-protective effects in ORG mice are associated with the lipid metabolism, especially in glycerophospholipid metabolism and the pantothenate/CoA synthesis pathways. EMPA's modulation of gut microbiota appears to be pivotal in suppressing glycerol 3-phosphate and CoA synthesis. The insights into gut microbiota-host metabolic interactions offer a novel therapeutic approach for ORG.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054662","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}
Pub Date : 2024-10-01Epub Date: 2024-08-26DOI: 10.1152/ajpcell.00452.2024
Georgina Louise Gardner, Jeffrey Alan Stuart
The tumor microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumors. Recently, "physiological" cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1%-8% O2). Nonetheless, further refinement of tumor-specific culture conditions may be needed. In this study, we describe the development of a tumor microenvironment medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumor interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumor-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared with plasma-like conditions (mouse plasma medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumor-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5% O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5% O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumor microenvironment-like conditions in standard cancer research. NEW & NOTEWORTHY Standard cell culture conditions do not replicate the complex tumor microenvironment experienced by cells in vivo. Although currently available plasma-like media are superior to traditional supraphysiological media, they fail to model tumor-like conditions. Using RNA-seq analysis and functional metabolic and migratory assays, we show that tumor microenvironment medium (TMEM), used with representative tumor hypoxia, better models cancerous phenotypes in culture. This emphasizes the critical importance of accurately modeling the tumor microenvironment in cancer research.
{"title":"Tumor microenvironment-like conditions alter pancreatic cancer cell metabolism and behavior.","authors":"Georgina Louise Gardner, Jeffrey Alan Stuart","doi":"10.1152/ajpcell.00452.2024","DOIUrl":"10.1152/ajpcell.00452.2024","url":null,"abstract":"<p><p>The tumor microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumors. Recently, \"physiological\" cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1%-8% O<sub>2</sub>). Nonetheless, further refinement of tumor-specific culture conditions may be needed. In this study, we describe the development of a tumor microenvironment medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumor interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumor-like conditions (TMEM, pH 7.0, 1.5% O<sub>2</sub>) exhibit profound differences in gene expression compared with plasma-like conditions (mouse plasma medium, pH 7.4, 5% O<sub>2</sub>). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumor-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5% O<sub>2</sub>/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5% O<sub>2</sub>/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumor microenvironment-like conditions in standard cancer research. <b>NEW & NOTEWORTHY</b> Standard cell culture conditions do not replicate the complex tumor microenvironment experienced by cells in vivo. Although currently available plasma-like media are superior to traditional supraphysiological media, they fail to model tumor-like conditions. Using RNA-seq analysis and functional metabolic and migratory assays, we show that tumor microenvironment medium (TMEM), used with representative tumor hypoxia, better models cancerous phenotypes in culture. This emphasizes the critical importance of accurately modeling the tumor microenvironment in cancer research.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054663","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}
Pub Date : 2024-10-01Epub Date: 2024-08-12DOI: 10.1152/ajpcell.00605.2023
Ken D Brandon, William E Frank, Kimberly M Stroka
Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature's specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics.
细胞依靠精确调节血管内的屏障功能来维持生理稳定和促进重要物质的运输。内皮细胞通过特化的粘连蛋白和紧密连接蛋白复合物实现这一功能,这些复合物控制着血管床的细胞旁通透性。粘连接头由 VE-粘连蛋白和相关的 catenins 固定在肌动蛋白细胞骨架上,介导对屏障完整性至关重要的同亲粘附。与此相反,由闭塞素、凝集素和连接粘附分子 A 组成的紧密连接与闭塞斑块蛋白相互作用,加强了对屏障选择性至关重要的细胞间连接。内皮细胞-细胞连接在发育、成熟和重塑过程中表现出动态构象,并受局部生化和机械线索的调节。这些结构调整在慢性炎症等疾病中起着关键作用,从癌症到心血管疾病,连接重塑都会导致血管通透性增加。相反,脑微血管的特殊交界排列由于其独特的分子组成和严密的组织结构,给治疗药物的输送带来了挑战。这篇评论探讨了内皮细胞-细胞连接构象的分子机制及其对血管通透性的影响。通过重点介绍在量化连接变化和了解机械传导途径方面的最新进展,我们阐明了细胞接触和血液动力学流动所产生的物理力是如何影响连接动态的。
{"title":"Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability.","authors":"Ken D Brandon, William E Frank, Kimberly M Stroka","doi":"10.1152/ajpcell.00605.2023","DOIUrl":"10.1152/ajpcell.00605.2023","url":null,"abstract":"<p><p>Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature's specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915846","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}