金玲
湖南省肿瘤医院 甲乳外科
Introduction: The adaptive immune response mediated by T cells plays a vital role in the initiation and maintenance of blood pressure (BP) elevation. Memory T cells, which are antigen-specific T cells, can respond specifically to repeated hypertensive stimuli. Although the roles of memory T cells in animal models are well studied, their maintenance and functions in hypertensive patients are poorly understood. Method: Here, we focused on the circulating memory T cells of hypertensive patients. By using single-cell RNA sequencing technology, subsets of memory T cells were identified. Differentially expressed genes (DEGs) and functional pathways were explored for related biological functions in each population of memory T cells. Result and Discussion: Our study identified four subsets of memory T cells in the blood of hypertensive patients, with CD8 effector memory T (TEM) cells accounting for more cells and demonstrating more biological functions than CD4 TEM cells. CD8 TEM cells were further analyzed using single-cell RNA sequencing technology, and subpopulation 1 was demonstrated to contribute to BP elevation. The key marker genes CKS2, PLIN2, and CNBP were identified and validated by mass-spectrum flow cytometry. Our data suggest that CD8 TEM cells as well as the marker genes could be preventive targets for patients with hypertensive cardiovascular disease.
Frontiers in cell and developmental biology 2023
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Circulation research 2021
BACKGROUND:Monogenic hypertension describe a series of hypertensive syndromes that are inherited by Mendelian laws. Sometimes genetic testing is required to provide evidence for their diagnoses, precise classification and targeted treatment. This study is the first to investigate the clinical utility of a causative gene screening and the combined yield of gene product expression analyses in cases with suspected monogenic hypertension.METHODS:We performed a large-scale multi-centre clinical genetic research of 1179 expertly selected hypertensive individuals from the Chinese Han population. Targeted sequencing were performed to evaluate 37 causative genes of potential cases of monogenic hypertension. Pathogenic and likely pathogenic variants were classified using the American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance (VUS) that had relatively high pathogenicity were selected and analysed using immunoblot protein expression assays.RESULTS:21 pathogenic or likely pathogenic variants were identified in 33 of 1179 cases (2.80%). Gene product expression analyses showed 27 VUSs harboured by 49 individuals (4.16%) could lead to abnormally expressed protein levels. Consequently, combining genetic screening with gene product expression analyses increased the diagnostic yield from 2.80% to 6.79%. The main aetiologies established were primary aldosteronism (PA; 27, 2.29%) and pheochromocytoma and paraganglioma (PPGL; 10, 0.85%).CONCLUSION:Molecular diagnoses obtained using causative gene screening combined with gene product expression analyses initially achieved a modest diagnostic yield. Our data highlight the predominant roles of PA and PPGL. Furthermore, we provide evidence indicating the enhanced diagnostic ability of combined genetic and functional evaluation.
Journal of medical genetics 2020
Aging is a universal and time dependent complex biological process, characterized by a progressive physiological dysfunction and an increased vulnerability to death. Though the physiological process of aging is still not fully understood, several cellular and molecular mechanisms have been identified. Long noncoding RNAs is a class of regulatory ncRNAs with transcript lengths >200 nucleotides. Discovery of this vast pool of regulators in mammalian genome supplies a new dimension to study and explore the aging process. In this review, we discuss the contribution of lncRNAs in aging and aging complications, and raise interest of serving lncRNAs as biomarkers and potential therapeutic targets to prolong health and ameliorate age-associated diseases. We hope understanding the roles of these high specificity and low conservation regulators in generating age-associated phenotypes might benefit human lifespan.
Biochimica et biophysica acta. Molecular basis of disease 2019
BACKGROUND:Establishing the diagnosis and determining disease activity of Takayasu arteritis (TA) remains challenging. Novel biomarkers might help to solve this problem.METHODS:In the screening phase, by using large-scale protein arrays detecting samples from 90 subjects (TA active, 29; TA inactive 31; and controls, 30). In the validation phase, by using enzyme-linked immunosorbent assay (ELISA), potential biomarkers for TA diagnosis, and activity classification were measured in independent cohorts, respectively.RESULTS:In the screening phase, 18 cytokines significantly differentially enriched between TA patients and controls and another 15 cytokines significantly differentially enriched between TA patient in active and inactive status were identified (adjusted P<0.05). In the validation phase, TIMP (tissue inhibitor of metalloproteinases)-1 was identified as a specific biomarker for TA diagnosis that a cutoff value of 221.86 μg/L could provide a specificity of 89.58% and a positive predictive value of 0.92. Meanwhile, we found it unreliable to use a single biomarker for TA activity classification. Considering this, we further built a logistic regression model based on multiple cytokines, including CA (cancer antigen) 125, FLRG (follistatin-related protein), IGFBP (insulin-like growth factor-binding protein)-2, CA15-3, GROa (growth-regulated alpha protein), LYVE (lymphatic vessel endothelial hyaluronic acid receptor)-1, ULBP (UL16-binding protein)-2, and CD (cluster of differentiation) 99, with an area under the curve reaching 0.909 for discriminating TA activity status.CONCLUSIONS:This study suggested TIMP-1 as a specific biomarker for TA diagnosis with a cutoff value of 221.86 μg/L. Furthermore, we provided a logistic regression model based on 8 biomarkers for the precisive activity classification of TA with an area under the curve of 0.909.
Circulation. Genomic and precision medicine 2019
Recent studies reported some long noncoding RNAs (lncRNAs)-mediated vascular smooth muscle cells (VSMCs) phenotypic switch, which was a common pathophysiological process of vascular diseases. However, whether human-specific expressed lncRNAs would modulate VSMCs phenotype and participate into the pathogenesis of essential hypertension remains unclear. By comparing the circulating lncRNAs expression profiles between hypertensive patients and healthy controls, we identified a lncRNA-AK098656, strongly upregulated in the plasma of hypertensive patients, and predominantly expressed in VSMCs. AK098656 promoted VSMCs synthetic phenotype evidenced by increasing VSMC proliferation and migration, elevating extracellular matrix proteins, whereas lowering contractile proteins. Furthermore, AK098656 was demonstrated to directly bind with the VSMCs-specific contractile protein, myosin heavy chain-11, and an essential component of extracellular matrix, fibronectin-1, and finally lowered these protein levels through protein degradation. AK098656 was also shown to bind with 26S proteasome non-ATPase regulatory subunit 11 and facilitated myosin heavy chain-11 to interact with this protein. In vivo, AK098656 transgenic rats showed spontaneous development of hypertension, with elevated VSMCs synthetic phenotype and narrowed resistant arteries. Transgenic rats also showed slight cardiac hypertrophy without other complications, which was similar with early pathophysiological changes of hypertension. All these data indicated AK098656 as a new human VSMC-dominant lncRNA, which could promote hypertension through accelerating contractile protein degradation, increasing VSMC synthetic phenotype, and finally narrowed resistance arteries.
Hypertension (Dallas, Tex. : 1979) 2018
Previous studies suggested a possible gut microbiota dysbiosis in chronic heart failure (CHF). However, direct evidence was lacking. In this study, we investigated the composition and metabolic patterns of gut microbiota in CHF patients to provide direct evidence and comprehensive understanding of gut microbiota dysbiosis in CHF. We enrolled 53 CHF patients and 41 controls. Metagenomic analyses of faecal samples and metabolomic analyses of faecal and plasma samples were then performed. We found that the composition of gut microbiota in CHF was significantly different from controls. Faecalibacterium prausnitzii decrease and Ruminococcus gnavus increase were the essential characteristics in CHF patients' gut microbiota. We also observed an imbalance of gut microbes involved in the metabolism of protective metabolites such as butyrate and harmful metabolites such as trimethylamine N-oxide in CHF patients. Metabolic features of both faecal and plasma samples from CHF patients also significantly changed. Moreover, alterations in faecal and plasma metabolic patterns correlated with gut microbiota dysbiosis in CHF. Taken together, we found that CHF was associated with distinct gut microbiota dysbiosis and pinpointed the specific core bacteria imbalance in CHF, along with correlations between changes in certain metabolites and gut microbes.
Scientific reports 2018
OBJECTIVES:CircRNAs, a novel class of noncoding RNAs, have been reported in many diseases. However, their role in hypertension remains unclear. Here, we aimed to determine the circRNA expression profile in hypertension patients and further construct a circRNA-miRNA-mRNA network for mechanism exploration.METHODS:Plasma circRNA expression profiles were screened by circRNA microarrays and verified by qRT-PCR method. CircRNA-miRNA-mRNA network was established to predict the circRNA targets. Gene ontology (GO) analysis and KEGG pathway analysis were applied for further enrichment of mRNA data.RESULTS:CircRNA microarrays study identified 13 downregulated and 46 upregulated circRNAs in hypertension patients, where four circRNAs (hsa-circ-0000437, hsa-circ-0008139, hsa-circ-0005870 and hsa-circ-0040809) showed significantly difference. By further validation, hsa-circ-0005870 exhibited significant downregulation in hypertensive patients. Then, we constructed a network of hsa-circ-0005870-targeted miRNAs, including hsa-miR-6807-3p, hsa-miR-5095, hsa-miR-1273g-3p, hsa-miR-5096, hsa-miR-619-5p, and their corresponding mRNAs. Gene oncology and KEGG pathway analysis enriched from specific mRNAs indicated the involvement of hsa-circ-0005870 in hypertension.CONCLUSIONS:In summary, hsa-circ-0005870 may represent a novel biomarker for the diagnosis of hypertension, and hsa-circ-0005870-miRNA-mRNA network may provide potential mechanism for hypertension.
Clinical and experimental hypertension (New York, N.Y. : 1993) 2017
