LncRNA LYPLAL1-DT in Type 2 Diabetes With Macrovascular Complication Contributes Protective Effects on Endothelial Cells via Regulating the miR-204-5p/SIRT1 Axis

Abstract Background: Long noncoding RNAs (lncRNAs) are involved in diabetes related diseases. However, the role of lncRNAs in the pathogenesis of type 2 diabetes with macrovascular complication (DMC) has seldomly been recognized. This study aimed to screen lncRNA profiles of leukocytes from DMC patients in order to explore the protective role of lncRNA LYPLAL1-DT in endothelial cells (EC) under high glucose (HG) and inflammatory conditions (IS).Methods: RNA sequencing was performed for critically pair-grouped blood samples of DMC patients and healthy control. Then the differentially expressed (DE) lncRNAs from circulating leukocytes were identified. Real-time PCR analyses were used to select the DE-lncRNAs within expanding cohorts. CCK8, transwell, Western blot, dual-luciferase system, and RIP were used to investigate the influence and molecular mechanisms of validated DE-lncRNAs in EC under HG and IS conditions. RNA sequencing was also used to identify DE-lncRNAs in exosomes isolated from the DMC serum and healthy control. Results: A total of 477 DE-lncRNAs were identified between DMC and healthy control. The enrichment and pathway analysis showed that most of them belonged to inflammatory, metabolic, and vascular diseases. A set of 12 of the 16 lncRNAs was validated as significant DE-lncRNAs in expanding cohorts. Furthermore, these DE-lncRNAs were shown to be significantly related to hypoxia, high glucose, and TNF-α stimulus (IS) in EC with an apparent metabolic memory of high glucose, especially novel lncRNA LYPLAL1-DT. LYPLAL1-DT overexpression results in the promotion of proliferation, migration of EC, as well as an elevation of autophagy under HG, and IS conditions. Overexpressed LYPLAL1-DT reduces the adhesion of monocytes to EC, boosts anti-inflammation, and suppresses inflammatory molecules secreted in the medium. Mechanistically, LYPLAL1-DT acts as ceRNA by downregulating miR-204-5p, therefore enhancing SIRT1 and protecting EC autophagy function; thus, alleviating apoptosis. Finally, exosome sequencing revealed LYPLAL1-DT expression was 4 times lower in DMC cells than in healthy samples. Conclusion: We identified 12 DE-lncRNAs related to DMC. Out of the 12 DE-lncRNAs lncRNA LYPLAL1-DT was identified to have protective effects on EC as ceRNA mediated through the miR-204-5p/SIRT1 pathway. Therefore, it inhibits the autophagy of EC as well as modulating systemic inflammation. This approach could be regarded as a new potential therapeutic target in DMC.

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Weighted Gene Coexpression Network Analysis Identified MicroRNA Coexpression Modules and Related Pathways in Type 2 Diabetes Mellitus

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9567641 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Tianyu Feng ◽

Kexin Li ◽

Pingping Zheng ◽

Yanjun Wang ◽

Yaogai Lv ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Network Analysis ◽

Rna Sequencing ◽

Gene Coexpression Network ◽

Gene Coexpression ◽

Coexpression Network Analysis

Objective. Type 2 diabetes mellitus (T2DM) is a metabolic disease with high incidence, which has seriously affected human life and health. MicroRNA, a short-chain noncoding RNA, plays an important role in T2DM. Identification of meaningful microRNA modules and the role of microRNAs provide a basis for searching potential biomarkers of T2DM. Materials and Methods. In this study, three newly diagnosed patients with T2DM and three controls were selected for Whole Peripheral Blood RNA Sequencing to establish a microRNA library. Weighted gene coexpression network analysis (WGCNA) was applied to construct coexpression modules and to detect the trait-related microRNA modules; then, KEGG enrichment analysis was performed to predict the biological function of the interest modules, and candidate hub microRNAs were screened out by the value of module membership (MM) and protein-protein interaction (PPI) network. Result. Four microRNA modules (blue, brown, magenta, and turquoise) were highly associated with the T2DM; the number of miRNAs in these modules ranged from 41 to 469. The Fc gamma R-mediated phagocytosis pathway, Rap1 signaling pathway, MAPK signaling pathway, and Lysosome pathway were common pathways in three of the four modules. RPS27A, UBC, and RAC1 were the top three proteins in our study; their corresponding RNAs were miR-1271-5p, miR-130a-3p, miR-130b-3p, and miR-574-3p. Conclusion. In summary, this study identified blood miRNAs in human T2DM using RNA sequencing. The findings may be the foundation for understanding the potential role of miRNAs in T2DM.

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Vascular Disease in Diabetic Women: Why Do They Miss the Female Protection?

Experimental Diabetes Research ◽

10.1155/2012/570598 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

Ana Paula Villela Dantas ◽

Zuleica Bruno Fortes ◽

Maria Helena Catelli de Carvalho

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 2 Diabetes Mellitus ◽

Vascular Disease ◽

Vascular Dysfunction ◽

Protective Effects ◽

Vascular Protection

Gender plays a pivotal role in the onset as well as in the progression of the cardiovascular disease with a higher morbidity and mortality being detected in men with respect to women. Type 2 Diabetes Mellitus (T2DM) may reduce gender-related differences in the prevalence of cardiovascular disease by fading the vascular protective effects afforded by estrogen in females. This article will discuss the role of sex and sex hormones on the incidence and mechanisms involved in vascular dysfunction associated to T2DM, which might explain why women with T2DM lack the vascular protection.

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Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2020.107647 ◽

2020 ◽

Vol 34 (9) ◽

pp. 107647 ◽

Cited By ~ 1

Author(s):

Milton Packer

Keyword(s):

Type 2 Diabetes ◽

Sglt2 Inhibitors ◽

Protective Effects

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Mechanisms of protective effects induced by blockade of the renin-angiotensin system: novel role of the pancreatic islet angiotensin-generating system in Type 2 diabetes

Diabetic Medicine ◽

10.1111/j.1464-5491.2007.02072.x ◽

2007 ◽

Vol 24 (2) ◽

pp. 110-116 ◽

Cited By ~ 34

Author(s):

P. S. Leung

Keyword(s):

Type 2 Diabetes ◽

Pancreatic Islet ◽

Renin Angiotensin System ◽

Protective Effects ◽

Angiotensin System ◽

Renin Angiotensin ◽

Generating System

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Interleukin-22 Might Act as a Double-Edged Sword in Type 2 Diabetes and Coronary Artery Disease

Mediators of Inflammation ◽

10.1155/2016/8254797 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 15

Author(s):

Fangchen Gong ◽

Jin Wu ◽

Ping Zhou ◽

Mengyao Zhang ◽

Jingning Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery Disease ◽

Endothelial Cells ◽

Coronary Artery ◽

Inflammatory Diseases ◽

Elevated Serum ◽

Low Grade ◽

Artery Disease

Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are both characterized by chronic low-grade inflammation. The role of Th17 and its related cytokines in T2DM and CAD is unclear. Here we investigated the serum levels of five Th17-related cytokines (IL-17, IL-22, MIP-3α, IL-9, and IL-27) in T2DM, CAD, and T2DM-CAD comorbidity patients. IL-22 was found to be elevated in all three conditions. Elevated serum IL-22 was independently associated with the incidence of T2DM and CAD. Conversely, IL-22 was found to protect endothelial cells from glucose- and lysophosphatidylcholine- (LPC-) induced injury, and IL-22R1 expression on endothelial cells was increased upon treatment with high glucose and LPC. Blocking of IL-22R1 with IL-22R1 antibody diminished the protective role of IL-22. Our results suggest that IL-22 functions as a double-edged sword in T2DM and CAD and that IL-22 may be used in the treatment of chronic inflammatory diseases such as T2DM and CAD.

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Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00400.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. E947-E957 ◽

Cited By ~ 41

Author(s):

Rui Wei ◽

Shifeng Ma ◽

Chen Wang ◽

Jing Ke ◽

Jin Yang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Cells ◽

Endothelial Function ◽

No Production ◽

Dependent Manner ◽

Protective Effects ◽

Newly Diagnosed ◽

Coronary Endothelial Function ◽

Enos Phosphorylation

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

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