Clinical science最新文献

{"title":"Myeloid cell-specific deletion of epidermal growth factor receptor aggravates acute cardiac injury.","authors":"Ama D Okyere, Tapas K Nayak, Viren Patwa, David Teplitsky, Erin McEachern, Rhonda L Carter, Heli Xu, Erhe Gao, Yan Zhou, Douglas G Tilley","doi":"10.1042/CS20230804","DOIUrl":"10.1042/CS20230804","url":null,"abstract":"<p><p>Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified as a mediator of macrophage responsiveness to select diseases, though its impact on cardiac function or remodeling following acute ischemic injury is unknown. We aimed to define the role of myeloid cell-specific EGFR in the regulation of cardiac function and remodeling following acute myocardial infarction (MI)-induced injury. Floxed EGFR mice were bred with homozygous LysM-Cre (LMC) transgenic mice to yield myeloid-specific EGFR knockout (mKO) mice. Via echocardiography, immunohistochemistry, RNA sequencing and flow cytometry, the impact of myeloid cell-specific EGFR deletion on cardiac structure and function was assessed at baseline and following injury. Compared with LMC controls, myeloid cell-specific EGFR deletion led to an increase in cardiomyocyte hypertrophy at baseline. Bulk RNASeq analysis of isolated cardiac Cd11b+ myeloid cells revealed substantial changes in mKO cell transcripts at baseline, particularly in relation to predicted decreases in neovascularization. In response to myocardial infarction, mKO mice experienced a hastened decline in cardiac function with isolated cardiac Cd11b+ myeloid cells expressing decreased levels of the pro-reparative mediators Vegfa and Il10, which coincided with enhanced cardiac hypertrophy and decreased capillary density. Overall, loss of EGFR qualitatively alters cardiac resident macrophages that promotes a low level of basal stress and a more rapid decrease in cardiac function along with worsened repair following acute ischemic injury.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 19","pages":"1513-1531"},"PeriodicalIF":6.0,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41110754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colchicine protects against the development of experimental abdominal aortic aneurysm.","authors":"Yi Zhao,&nbsp;Qi-Rui Shen,&nbsp;Yu-Xin Chen,&nbsp;Yu Shi,&nbsp;Wen-Bing Wu,&nbsp;Qiao Li,&nbsp;Dong-Jie Li,&nbsp;Fu-Ming Shen,&nbsp;Hui Fu","doi":"10.1042/CS20230499","DOIUrl":"10.1042/CS20230499","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is characterized by at least 1.5-fold enlargement of the infrarenal aorta, a ruptured AAA is life-threatening. Colchicine is a medicine used to treat gout and familial Mediterranean fever, and recently, it was approved to reduce the risk of cardiovascular events in adult patients with established atherosclerotic disease. With an AAA mice model created by treatment with porcine pancreatic elastase (PPE) and β-aminopropionitrile (BAPN), this work was designed to explore whether colchicine could protect against the development of AAA. Here, we showed that colchicine could limit AAA formation, as evidenced by the decreased total aortic weight per body weight, AAA incidence, maximal abdominal aortic diameter and collagen deposition. We also found that colchicine could prevent the phenotypic switching of vascular smooth muscle cells from a contractile to synthetic state during AAA. In addition, it was demonstrated that colchicine was able to reduce vascular inflammation, oxidative stress, cell pyroptosis and immune cells infiltration to the aortic wall in the AAA mice model. Finally, it was proved that the protective action of colchicine against AAA formation was mainly mediated by preventing immune cells infiltration to the aortic wall. In summary, our findings demonstrated that colchicine could protect against the development of experimental AAA, providing a potential therapeutic strategy for AAA intervention in the clinic.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 19","pages":"1533-1545"},"PeriodicalIF":6.0,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transferrin promotes chondrogenic differentiation in condylar growth through inducing autophagy via ULK1-ATG16L1 axis.","authors":"Xi Wen,&nbsp;Yixiang Wang,&nbsp;Yan Gu","doi":"10.1042/CS20230544","DOIUrl":"10.1042/CS20230544","url":null,"abstract":"<p><p>Skeletal mandibular hypoplasia (SMH) is one of the most common skeletal craniofacial deformities in orthodontics, which was often accompanied by impaired chondrogenesis and increasing apoptosis of condylar chondrocytes. Therefore, protecting chondrocytes from apoptosis and promoting chondrogenesis in condylar growth is vital for treatment of SMH patients. Transferrin (TF) was highly expressed in condylar cartilage of newborn mice and was gradually declined as the condyle ceased growing. Interestingly, serum level of TF in SMH patients was significantly lower than normal subjects. Hence, the aim of our study was to investigate the effect of TF on survival and differentiation of chondrocytes and condylar growth. First, we found that TF protected chondrogenic cell line ATDC5 cells from hypoxia-induced apoptosis and promoted proliferation and chondrogenic differentiation in vitro. Second, TF promoted chondrogenic differentiation and survival through activating autophagic flux. Inhibiting autophagic flux markedly blocked the effects of TF. Third, TF significantly activated ULK1-ATG16L1 axis. Silencing either transferrin receptor (TFRC), ULK1/2 or ATG16 significantly blocked the autophagic flux induced by TF, as well as its effect on anti-apoptosis and chondrogenic differentiation. Furthermore, we established an organoid culture model of mandible ex vivo and found that TF significantly promoted condylar growth. Taken together, our study unraveled a novel function of TF in condylar growth that TF protected chondrocytes from hypoxia-induced apoptosis and promoted chondrogenic differentiation through inducing autophagy via ULK1-ATG16L1 axis, which demonstrated that TF could be a novel growth factor of condylar growth and shed new light on developing treatment strategy of SMH patients.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1431-1449"},"PeriodicalIF":6.0,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10205924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Edema and lymphatic clearance: molecular mechanisms and ongoing challenges.","authors":"Jerome W Breslin","doi":"10.1042/CS20220314","DOIUrl":"10.1042/CS20220314","url":null,"abstract":"<p><p>Resolution of edema remains a significant clinical challenge. Conditions such as traumatic shock, sepsis, or diabetes often involve microvascular hyperpermeability, which leads to tissue and organ dysfunction. Lymphatic insufficiency due to genetic causes, surgical removal of lymph nodes, or infections, leads to varying degrees of tissue swelling that impair mobility and immune defenses. Treatment options are limited to management of edema as there are no specific therapeutics that have demonstrated significant success for ameliorating microvascular leakage or impaired lymphatic function. This review examines current knowledge about the physiological, cellular, and molecular mechanisms that control microvascular permeability and lymphatic clearance, the respective processes for interstitial fluid formation and removal. Clinical conditions featuring edema, along with potential future directions are discussed.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 18","pages":"1451-1476"},"PeriodicalIF":6.0,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11025659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41103201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome-based exploration of potential molecular targets and mechanisms of selenomethionine in alleviating renal ischemia-reperfusion injury.","authors":"Jun Pei,&nbsp;Xiaomao Tian,&nbsp;Chengjun Yu,&nbsp;Jin Luo,&nbsp;Yifan Hong,&nbsp;Jie Zhang,&nbsp;Sheng Wen,&nbsp;Yi Hua,&nbsp;Guanghui Wei","doi":"10.1042/CS20230818","DOIUrl":"10.1042/CS20230818","url":null,"abstract":"<p><p>Renal ischemia-reperfusion injuries (IRIs) are one of the leading causes of acute kidney injuries (AKIs). Selenium, as an essential trace element, is able to antioxidant stress and reduces inflammatory responses. The regulation mechanism of selenomethionine, one of the major forms of selenium intake by humans, is not yet clear in renal IRIs. Therefore, we aimed to explore the key targets and related mechanisms of selenomethionine regulation in renal IRIs and provide new ideas for the treatment of selenomethionine with renal IRIs. We used transcriptome sequencing data from public databases as well as animal experiments to explore the key target genes and related mechanisms regulated by selenomethionine in renal IRI. We found that selenomethionine can effectively alleviate renal IRI by a mechanism that may be achieved by inhibiting the MAPK signaling pathway. Meanwhile, we also found that the key target of selenomethionine regulation in renal IRI might be selenoprotein GPX3 based on the PPI protein interaction network and machine learning. Through a comprehensive analysis of bioinformatic techniques and animal experiments, we found that Gpx3 might serve as a key gene for the regulation of selenomethionine in renal IRIs. Selenomethionine may exert a protective effect against renal IRI by up-regulating GPX3, inhibiting the MAPK signaling pathway, increased production of antioxidants, decreasing inflammation levels, mitigation of apoptosis in renal tubular epithelial cells, this reduces renal histopathological damage and protects renal function. Providing a theoretical basis for the mechanism of selenomethionine actions in renal IRIs.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1477-1498"},"PeriodicalIF":6.0,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10235559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-17D produced by alveolar epithelial type II cells alleviates LPS-induced acute lung injury via the Nrf2 pathway.","authors":"Shuan Dong,&nbsp;Shasha Liu,&nbsp;Qiaoying Gao,&nbsp;Jia Shi,&nbsp;Kai Song,&nbsp;Ya Wu,&nbsp;Huayang Liu,&nbsp;Chenxu Guo,&nbsp;Yan Huang,&nbsp;Shihan du,&nbsp;Xiangyun Li,&nbsp;Lixiu Ge,&nbsp;Jianbo Yu","doi":"10.1042/CS20230354","DOIUrl":"10.1042/CS20230354","url":null,"abstract":"<p><strong>Background: </strong>Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated interleukin-17D (IL-17D), is notably abundant within pulmonary confines. Nevertheless, its implication in sepsis remains somewhat enigmatic. The present study endeavors to scrutinize the participation of IL-17D in sepsis-induced acute lung injury (ALI).</p><p><strong>Methods: </strong>The levels of IL-17D in the serum and bronchoalveolar lavage fluid (BALF) of both healthy cohorts and septic patients were ascertained through an ELISA protocol. For the creation of a sepsis-induced ALI model, intraperitoneal lipopolysaccharide (LPS) injections were administered to male C57/BL6 mice. Subsequently, we examined the fluctuations and repercussions associated with IL-17D in sepsis-induced ALI, probing its interrelation with nuclear factor erythroid 2-related factor 2 (Nrf2), alveolar epithelial permeability, and heme oxygenase-1.</p><p><strong>Results: </strong>IL-17D levels exhibited significant reduction both in the serum and BALF of septic patients (P<0.001). Similar observations manifested in mice subjected to LPS-induced acute lung injury (ALI) (P=0.002). Intraperitoneal administration of recombinant interleukin 17D protein (rIL-17D) prompted increased expression of claudin 18 and concomitant enhancement of alveolar epithelial permeability, thus, culminating in improved lung injury (P<0.001). Alveolar epithelial type II (ATII) cells were identified as the source of IL-17D, regulated by Nrf2. Furthermore, a deficiency in HO-1 yielded elevated IL-17D levels (P=0.004), albeit administration of rIL-17D ameliorated the exacerbated pulmonary damage resulting from HO-1 deficiency.</p><p><strong>Conclusion: </strong>Nrf2 fosters IL-17D production within AT II cells, thereby conferring a protective role in sepsis-induced ALI.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1499-1512"},"PeriodicalIF":6.0,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10243527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress.","authors":"Luís F Grilo,&nbsp;João D Martins,&nbsp;Mariana S Diniz,&nbsp;Carolina Tocantins,&nbsp;Chiara H Cavallaro,&nbsp;Inês Baldeiras,&nbsp;Teresa Cunha-Oliveira,&nbsp;Stephen Ford,&nbsp;Peter W Nathanielsz,&nbsp;Paulo J Oliveira,&nbsp;Susana P Pereira","doi":"10.1042/CS20230048","DOIUrl":"10.1042/CS20230048","url":null,"abstract":"<p><p>Maternal obesity (MO) is rising worldwide, affecting half of all gestations, constituting a possible risk-factor for some pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress (OS) and mitochondrial dysfunction. Maternal hepatic disease increases maternal and fetal morbidity and mortality. Understanding the role of MO on liver function and pathophysiology could be crucial for better understanding the altered pathways leading to PALD and liver disease, possibly paving the way to prevention and adequate management of disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes (fed 150% of recommended nutrition starting 60 days before conception). Maternal hepatic redox state, mitochondrial respiratory chain (MRC), and OS markers were investigated. MO decreased MRC complex-II activity and its subunits SDHA and SDHB protein expression, increased complex-I and complex-IV activities despite reduced complex-IV subunit mtCO1 protein expression, and increased ATP synthase ATP5A subunit. Hepatic MO-metabolic remodeling was characterized by decreased adenine nucleotide translocator 1 and 2 (ANT-1/2) and voltage-dependent anion channel (VDAC) protein expression and protein kinase A (PKA) activity (P<0.01), and augmented NAD+/NADH ratio due to reduced NADH levels (P<0.01). MO showed an altered redox state with increased OS, increased lipid peroxidation (P<0.01), decreased GSH/GSSG ratio (P=0.005), increased superoxide dismutase (P=0.03) and decreased catalase (P=0.03) antioxidant enzymatic activities, lower catalase, glutathione peroxidase (GPX)-4 and glutathione reductase protein expression (P<0.05), and increased GPX-1 abundance (P=0.03). MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 17","pages":"1347-1372"},"PeriodicalIF":6.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10146767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14 inhibits malignant progression of oral squamous cell carcinoma by targeting the autophagy-related gene RB1CC1 in an m6A-IGF2BP2-dependent manner.","authors":"Jianfeng Liang,&nbsp;Hongshi Cai,&nbsp;Chen Hou,&nbsp;Fan Song,&nbsp;Yaoqi Jiang,&nbsp;Ziyi Wang,&nbsp;Danqi Qiu,&nbsp;Yue Zhu,&nbsp;Fang Wang,&nbsp;Dongsheng Yu,&nbsp;Jinsong Hou","doi":"10.1042/CS20230219","DOIUrl":"10.1042/CS20230219","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) plays crucial roles in tumorigenesis and autophagy. However, the underlying mechanisms mediated by m6A and autophagy in the malignant progression of oral squamous cell carcinoma (OSCC) remain unclear. In the present study, we revealed that down-regulated expression of METTL14 was correlated with advanced clinicopathological characteristics and poor prognosis in OSCC. METTL14 knockdown significantly inhibited autophagy and facilitated malignant progression in vitro, and promoted tumor growth and metastasis in vivo. A cell model of rapamycin-induced autophagy was established to identify RB1CC1 as a potential target gene involved in m6A-regulated autophagy in OSCC, through RNA sequencing and methylated RNA immunoprecipitation sequencing (meRIP-seq) analysis. Mechanistically, we confirmed that METTL14 posttranscriptionally enhanced RB1CC1 expression in an m6A-IGF2BP2-dependent manner, thereby affecting autophagy and progression in OSCC, through methylated RNA immunoprecipitation qRT-PCR (meRIP-qPCR), RNA stability assays, mutagenesis assays and dual-luciferase reporter. Collectively, our findings demonstrated that METTL14 serves as an OSCC suppressor by regulating the autophagy-related gene RB1CC1 through m6A modification, which may provide a new insight for the diagnosis and therapy of OSCC.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 17","pages":"1373-1389"},"PeriodicalIF":6.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/54/cs-137-cs20230219.PMC10500204.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10624400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise ameliorates skeletal muscle insulin resistance by modulating GRK4-mediated D1R expression.","authors":"Yu Tao,&nbsp;Wenbin Luo,&nbsp;Yue Chen,&nbsp;Caiyu Chen,&nbsp;Shengnan Chen,&nbsp;Xiaoping Li,&nbsp;Ken Chen,&nbsp;Chunyu Zeng","doi":"10.1042/CS20230664","DOIUrl":"10.1042/CS20230664","url":null,"abstract":"<p><p>Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as fenoldopam, could improve peripheral insulin sensitivity, while antipsychotics, which are dopamine receptor antagonists, increased susceptibility to Type 2 diabetes mellitus (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the up-regulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, the present study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 17","pages":"1391-1407"},"PeriodicalIF":6.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10200714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B- and T-lymphocyte attenuator could be a new player in accelerated atherosclerosis associated with chronic kidney disease.","authors":"Nuria Dolade,&nbsp;Sandra Rayego-Mateos,&nbsp;Alicia Garcia-Carrasco,&nbsp;Maryse Guerin,&nbsp;Jose-Luis Martín-Ventura,&nbsp;Marta Ruiz-Ortega,&nbsp;Pierre-Louis Tharaux,&nbsp;Jose Manuel Valdivielso","doi":"10.1042/CS20230399","DOIUrl":"10.1042/CS20230399","url":null,"abstract":"<p><strong>Background: </strong>In chronic kidney disease (CKD), cardiovascular morbi-mortality is higher than in general population. Atherosclerotic cardiovascular disease is accelerated in CKD, but specific CKD-related risk factors for atherosclerosis are unknown.</p><p><strong>Methods: </strong>CKD patients from the NEFRONA study were used. We performed mRNA array from blood of patients free from atheroma plaque at baseline, with (n=10) and without (n=10) de novo atherosclerotic plaque development 2 years later. Selected mRNA candidates were validated in a bigger sample (n=148). Validated candidates were investigated in vivo in an experimental model of CKD-accelerated atherosclerosis, and in vitro in murine macrophages.</p><p><strong>Results: </strong>mRNA array analysis showed 92 up-regulated and 67 down-regulated mRNAs in samples from CKD patients with de novo plaque development. The functional analysis pointed to a paramount role of the immune response. The validation in a bigger sample confirmed that B- and T-lymphocyte co-inhibitory molecule (BTLA) down-regulation was associated with de novo plaque presence after 2 years. However, BTLA down-regulation was not found to be associated with atherosclerotic progression in patients with plaque already present at baseline. In a model of CKD-accelerated atherosclerosis, mRNA and protein expression levels of BTLA were significantly decreased in blood samples and atheroma plaques. Plaques from animals with CKD were bigger, had more infiltration of inflammatory cells, higher expression of IL6 and IL17 and less presence of collagen than plaques from control animals. Incubation of macrophages with rat uremic serum decreased BTLA expression.</p><p><strong>Conclusions: </strong>BTLA could be a potential biomarker or therapeutic target for atherosclerosis incidence in CKD patients.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"137 17","pages":"1409-1429"},"PeriodicalIF":6.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10242336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}