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Li T, Qian Y, Li H, Wang T, Jiang Q, Wang Y, Zhu Y, Li S, He X, Shi G, Su W, Lu Y, Chen Y. Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion. Cell Commun Signal 2024; 22:275. [PMID: 38755602 PMCID: PMC11097549 DOI: 10.1186/s12964-024-01653-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated. METHODS We first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells. RESULTS We detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils. CONCLUSION In this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.
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Affiliation(s)
- Ting Li
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yixia Qian
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Haicheng Li
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Tongtong Wang
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Qi Jiang
- Department of Ocular Immunology & Uveitis, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510515, China
| | - Yuchan Wang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yanhua Zhu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Shasha Li
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Xuemin He
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Guojun Shi
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Wenru Su
- Department of Ocular Immunology & Uveitis, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510515, China
| | - Yan Lu
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Yanming Chen
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
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Guan H, Tian J, Wang Y, Niu P, Zhang Y, Zhang Y, Fang X, Miao R, Yin R, Tong X. Advances in secondary prevention mechanisms of macrovascular complications in type 2 diabetes mellitus patients: a comprehensive review. Eur J Med Res 2024; 29:152. [PMID: 38438934 PMCID: PMC10910816 DOI: 10.1186/s40001-024-01739-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/21/2024] [Indexed: 03/06/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) poses a significant global health burden. This is particularly due to its macrovascular complications, such as coronary artery disease, peripheral vascular disease, and cerebrovascular disease, which have emerged as leading contributors to morbidity and mortality. This review comprehensively explores the pathophysiological mechanisms underlying these complications, protective strategies, and both existing and emerging secondary preventive measures. Furthermore, we delve into the applications of experimental models and methodologies in foundational research while also highlighting current research limitations and future directions. Specifically, we focus on the literature published post-2020 concerning the secondary prevention of macrovascular complications in patients with T2DM by conducting a targeted review of studies supported by robust evidence to offer a holistic perspective.
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Affiliation(s)
- Huifang Guan
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Jiaxing Tian
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
| | - Ying Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Ping Niu
- Rehabilitation Department, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Yuxin Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yanjiao Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xinyi Fang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
- Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Runyu Miao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
- Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Ruiyang Yin
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xiaolin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Xiang ZY, Chen SL, Qin XR, Lin SL, Xu Y, Lu LN, Zou HD. Changes and related factors of blood CCN1 levels in diabetic patients. Front Endocrinol (Lausanne) 2023; 14:1131993. [PMID: 37334311 PMCID: PMC10273100 DOI: 10.3389/fendo.2023.1131993] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 05/15/2023] [Indexed: 06/20/2023] Open
Abstract
Objective To study the differences in blood cellular communication network factor 1 (CCN1) levels between patients with diabetes mellitus (DM) and healthy individuals and to explore the relationship between CCN1 and diabetic retinopathy (DR). Methods Plasma CCN1 levels were detected using ELISA in 50 healthy controls, 74 patients with diabetes without diabetic retinopathy (DM group), and 69 patients with diabetic retinopathy (DR group). Correlations between CCN1 levels and age, body mass index, mean arterial pressure, hemoglobin A1c, and other factors were analyzed. The relationship between CCN1 expression and DR was explored using logistic regression after adjusting for confounding factors. Blood mRNA sequencing analysis was performed for all subjects, and the molecular changes that may be related to CCN1 were explored. The retinal vasculature of streptozotocin-induced diabetic rats was examined using fundus fluorescein angiography; in addition, retinal protein expression was examined using western blotting. Results Plasma CCN1 levels in patients with DR were significantly higher than in the control and DM groups; however, no significant differences were observed between healthy controls and patients with DM. CCN1 levels negatively correlated with body mass index and positively correlated with the duration of diabetes and urea levels. It was observed that high (OR 4.72, 95% CI: 1.10-20.25) and very high (OR 8.54, 95% CI: 2.00-36.51) levels of CCN1 were risk factors for DR. Blood mRNA sequencing analysis revealed that CCN1-related pathways were significantly altered in the DR group. The expression of hypoxia-, oxidative stress-, and dephosphorylation-related proteins were elevated, while that of tight junction proteins were reduced in the retinas of diabetic rats. Conclusion Blood CCN1 levels are significantly elevated in patients with DR. High and very high levels of plasma CCN1 are risk factors for DR. Blood CCN1 level may be a potential biomarker for diagnosis of DR. The effects of CCN1 on DR may be related to hypoxia, oxidative stress, and dephosphorylation.
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Affiliation(s)
- Zhao-Yu Xiang
- National Clinical Research Center for Eye Diseases, Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
| | - Shu-Li Chen
- National Clinical Research Center for Eye Diseases, Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
| | - Xin-Ran Qin
- National Clinical Research Center for Eye Diseases, Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
| | - Sen-Lin Lin
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
| | - Yi Xu
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
| | - Li-Na Lu
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
| | - Hai-Dong Zou
- National Clinical Research Center for Eye Diseases, Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China
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Pervaiz N, Kathuria I, Aithabathula RV, Singla B. Matricellular proteins in atherosclerosis development. Matrix Biol 2023; 120:1-23. [PMID: 37086928 PMCID: PMC10225360 DOI: 10.1016/j.matbio.2023.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 04/24/2023]
Abstract
The extracellular matrix (ECM) is an intricate network composed of various multi-domain macromolecules like collagen, proteoglycans, and fibronectin, etc., that form a structurally stable composite, contributing to the mechanical properties of tissue. However, matricellular proteins are non-structural, secretory extracellular matrix proteins, which modulate various cellular functions via interacting with cell surface receptors, proteases, hormones, and cell-matrix. They play essential roles in maintaining tissue homeostasis by regulating cell differentiation, proliferation, adhesion, migration, and several signal transduction pathways. Matricellular proteins display a broad functionality regulated by their multiple structural domains and their ability to interact with different extracellular substrates and/or cell surface receptors. The expression of these proteins is low in adults, however, gets upregulated following injuries, inflammation, and during tumor growth. The marked elevation in the expression of these proteins during atherosclerosis suggests a positive association between their expression and atherosclerotic lesion formation. The role of matricellular proteins in atherosclerosis development has remained an area of research interest in the last two decades and studies revealed these proteins as important players in governing vascular function, remodeling, and plaque formation. Despite extensive research, many aspects of the matrix protein biology in atherosclerosis are still unknown and future studies are required to investigate whether targeting pathways stimulated by these proteins represent viable therapeutic approaches for patients with atherosclerotic vascular diseases. This review summarizes the characteristics of distinct matricellular proteins, discusses the available literature on the involvement of matrix proteins in the pathogenesis of atherosclerosis and suggests new avenues for future research.
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Affiliation(s)
- Naveed Pervaiz
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, USA
| | - Ishita Kathuria
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, USA
| | - Ravi Varma Aithabathula
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, USA
| | - Bhupesh Singla
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, USA.
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Song Y, Zhao Y, Bai X, Cheng W, Wang L, Shu M, Shu Y, Zhang L, Jin S. Remnant cholesterol is independently asssociated with an increased risk of peripheral artery disease in type 2 diabetic patients. Front Endocrinol (Lausanne) 2023; 14:1111152. [PMID: 36875452 PMCID: PMC9974817 DOI: 10.3389/fendo.2023.1111152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Remnant cholesterol (RC) has been correlated with a higher risk of atherosclerosis. It has been confirmed that in the general population, an elevated RC level is related to a 5-fold higher risk of peripheral arterial disease (PAD). Diabetes is one of the strongest risk factors for PAD development. However, the association between RC and PAD in the specific population of type 2 diabetes mellitus (T2DM) has not been investigated. Herein, the correlation was investigated between RC and PAD in T2DM patients. METHODS In the retrospective study, the hematological parameter data of 246 T2DM patients without PAD (T2DM - WPAD) and 270 T2DM patients with PAD (T2DM - PAD) was collected. Differences in RC levels between the two groups were compared, and the association between RC and PAD severity was examined. Multifactorial regression was used to determine whether RC was a significant contributor to the development of T2DM - PAD. The diagnostic potential of RC was tested using receiver operating characteristic (ROC) curve. RESULTS The RC levels in T2DM - PAD individuals were considerably greater than in T2DM - WPAD individuals (P < 0.001). RC had a positive correlation with disease severity. Further, multifactorial logistic regression analyses found that elevated RC levels were a major contributor to T2DM - PAD (P < 0.001). The area under the curve (AUC) of the RC for T2DM - PAD patients was 0.727. The cut-off value of RC was 0.64 mmol/L. CONCLUSION The RC levels were higher in T2DM - PAD patients, and were independently linked with its severity. Diabetic patients with RC levels > 0.64 mmol/L had an elevated risk of developing PAD.
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Affiliation(s)
- Yi Song
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Zhao
- Geriatric Medicine Center, Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Department of Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xiangli Bai
- Department of Laboratory Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenzhuo Cheng
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Wang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Shu
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Shu
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liyin Zhang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Si Jin
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Si Jin,
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Song Y, Zhao Y, Shu Y, Zhang L, Cheng W, Wang L, Shu M, Xue B, Wang R, Feng Z, Yin Y, Yu F, Jin S. Combination model of neutrophil to high-density lipoprotein ratio and system inflammation response index is more valuable for predicting peripheral arterial disease in type 2 diabetic patients: A cross-sectional study. Front Endocrinol (Lausanne) 2023; 14:1100453. [PMID: 36875480 PMCID: PMC9978802 DOI: 10.3389/fendo.2023.1100453] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 02/01/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Neutrophil/high-density lipoprotein (HDL) ratio (NHR), monocyte/HDL ratio (MHR), lymphocyte/HDL ratio (LHR), platelet/HDL ratio (PHR), systemic immune-inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) have been recently investigated as novel inflammatory markers. Herein, the correlation was investigated between these inflammatory biomarkers and peripheral arterial disease (PAD) in type 2 diabetes mellitus (T2DM) patients. METHODS In this retrospective observational study, the hematological parameter data of 216 T2DM patients without PAD (T2DM-WPAD) and 218 T2DM patients with PAD (T2DM-PAD) at Fontaine stages II, III or IV stage had been collected. Differences in NHR, MHR, LHR, PHR, SII, SIRI, and AISI were analyzed, and receiver operating characteristic (ROC) curves were used to analyze the diagnostic potential of these parameters. RESULTS The levels of NHR, MHR, PHR, SII, SIRI and AISI in T2DM-PAD patients were significantly higher than in T2DM-WPAD patients (P < 0.001). They were correlated with disease severity. Further, multifactorial logistic regression analyses showed that higher NHR, MHR, PHR, SII, SIRI, and AISI might be independent risk factors for T2DM-PAD (P < 0.001). The areas under the curve (AUCs) of the NHR, MHR, PHR, SII, SIRI, and AISI for T2DM-PAD patients was 0.703, 0.685, 0.606, 0.648, 0.711, and 0.670, respectively. The AUC of the NHR and SIRI combined model was 0.733. CONCLUSION The levels of NHR, MHR, PHR, SII, SIRI, and AISI were higher in T2DM-PAD patients, and they were independently linked with its clinical severity. The combination model of NHR and SIRI was most valuable for predicting T2DM - PAD.
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Affiliation(s)
- Yi Song
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Zhao
- Geriatric Medicine Center, Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Department of Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Yan Shu
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liyin Zhang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenzhuo Cheng
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Wang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Shu
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baorui Xue
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruonan Wang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziyun Feng
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yao Yin
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fangyang Yu
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Si Jin
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Si Jin,
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Li W, Li Y, Zhi W, Liu C, Fan W, Miao Q, Gu X. Diagnostic value of using exosome-derived cysteine-rich protein 61 as biomarkers for acute coronary syndrome. Exp Ther Med 2021; 22:1437. [PMID: 34721679 PMCID: PMC8549088 DOI: 10.3892/etm.2021.10872] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/05/2021] [Indexed: 12/15/2022] Open
Abstract
Acute coronary syndrome (ACS) is the main manifestation of cardiovascular disease and the primary cause of adult hospitalization in China. There is an urgent demand for novel biomarkers for the diagnosis of ACS. Although plasma cysteine-rich protein 61 (Cyr61) has been previously reported to be accurate for ACS diagnosis, the accuracy of exosomal Cyr61 in ACS diagnosis remains unknown. In the present study, the aim was to assess the potential of applying exosomal Cyr61 in ACS diagnosis and to explore the role of Cyr61 in vascular remodeling in vitro. The abundance of Cyr61 in plasma-derived exosomes from patients with unstable angina pectoris (UAP), acute myocardial infarction (AMI) patients in addition to those isolated from healthy individuals were detected using an ELISA kit. The association between exosomal Cyr61 levels and clinical characteristics of ACS patients was analyzed through χ2 test, Fisher's exact test and Student's t-test. Receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using exosomal Cyr61 as a biomarker of ACS diagnosis. Furthermore, independent predictors of the existence of ACS were investigated through a multivariate analysis. Subsequently, the role of Cyr61 on vascular remodeling was evaluated in vascular smooth muscle cells (VSMCs) upon oxidized low-density lipoprotein (ox-LDL) treatment by performing Cyr61 knockdown, Cell Counting Kit-8, flow cytometry and Transwell assays. Exosomal Cyr61 expression was found to be significantly elevated in patients with ACS compared with that in healthy individuals. In addition, exosomal Cyr61 levels were associated with sex, family history of ACS and glucose levels. ROC curve analyzes revealed that exosomal Cyr61 expression could be used to differentiate patients with UAP, AMI and ACS from healthy individuals. Furthermore, exosomal Cyr61 levels were independently correlated with the existence of ACS. In vitro, Cyr61 expression was demonstrated to be significantly increased in VSMCs after ox-LDL exposure in a concentration- and time-dependent manner. Functionally, the elevated cell viability and migration of VSMCs induced by ox-LDL were partially but significantly inhibited by Cyr61 knockdown. By contrast, knocking down Cyr61 expression significantly elevated the apoptosis rate of VSMCs compared with that in the ox-LDL-treated group. In conclusion, data from the present study suggest that Cyr61 serve a regulatory role in vascular remodeling in vitro, where exosomal Cyr61 levels may represent a promising biomarker for ACS diagnosis.
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Affiliation(s)
- Wei Li
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Yi Li
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Wei Zhi
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Chen Liu
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Weize Fan
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Qing Miao
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xinshun Gu
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Li H, Li T, Wang H, He X, Li Y, Wen S, Peng R, Nie Y, Lu Y, Yang H, Ye Y, Shi G, Chen Y. Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression. Front Cardiovasc Med 2021; 8:689318. [PMID: 34458333 PMCID: PMC8385274 DOI: 10.3389/fcvm.2021.689318] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose: Diabetic retinopathy (DR) is one of the most common diabetic microvascular complications. However, the pathogenesis of DR has not yet been fully elucidated. This study aimed to discover novel and key molecules involved in the pathogenesis of DR, which could potentially be targets for therapeutic DR intervention. Methods: To identify potential genes involved in the pathogenesis of DR, we analyzed the public database of neovascular membranes (NVMs) from patients with proliferative diabetic retinopathy (PDR) and healthy controls (HCs) (GSE102485, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102485). Further, we compared these findings by performing RNA-sequencing analysis of peripheral blood mononuclear cells (PBMC) from patients with DR, control patients with non-complicated diabetes mellitus (DMC), and HCs. To determine the critical role of candidate genes in DR, knockdown or knockout was performed in human retinal vascular endothelial cells (HRVECs). The oxidative stress pathway, as well as tight junction integrity, was analyzed. Results: Transcriptional profiles showed distinct patterns between the NVMs of patients with DR and those of the HCs. Those genes enriched in either extracellular matrix (ECM)-receptor interaction or focal adhesion pathways were considerably upregulated. Both pathways were important for maintaining the integrity of retinal vascular structure and function. Importantly, the gene encoding the matricellular protein CCN1, a key gene in cell physiology, was differentially expressed in both pathways. Knockdown of CCN1 by small interfering RNA (siRNA) or knockout of CCN1 by the CRISPR-Cas9 technique in HRVECs significantly increased the levels of VE-cadherin, reduced the level of NADPH oxidase 4 (NOX4), and inhibited the generation of reactive oxygen species (ROS). Conclusion: The present study identifies CCN1 as an important regulator in the pathogenesis of DR. Increased expression of CCN1 stimulates oxidative stress and disrupts tight junction integrity in endothelial cells by inducing NOX4. Thus, targeting the CCN1/NOX4 axis provides a therapeutic strategy for treating DR by alleviating endothelial cell injury.
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Affiliation(s)
- Haicheng Li
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ting Li
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Heting Wang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xuemin He
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ying Li
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Siying Wen
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Rongdong Peng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuanpeng Nie
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yan Lu
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - He Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Yinong Ye
- Foshan Fourth People's Hospital, Foshan, China
| | - Guojun Shi
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yanming Chen
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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