Vascular actions of insulin with implications for endothelial dysfunction

Hemodynamic actions of insulin depend largely on the hormone's ability to stimulate synthesis and release of endothelial mediators, whose balanced activity ensures dynamic control of vascular function. Nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) are important examples of endothelial mediators with opposing properties on vascular tone, hemostatic processes, and vascular permeability. Reduced NO bioavailability, resulting from either insufficient production or increased degradation of NO, characterizes endothelial dysfunction. In turn, endothelial dysfunction predicts vascular complications of metabolic and hemodynamic disorders. In the cardiovascular system, insulin stimulates the production and release of NO, ET-1, and ROS via activation of distinct intracellular signaling pathways. Under insulin-resistant conditions, increased insulin concentrations and/or impaired insulin-signaling pathways in the vasculature may contribute to imbalance in secretion of endothelial mediators that promote pathogenesis of vascular abnormalities. This short review describes signaling pathways involved in insulin-stimulated release of NO, ROS, and ET-1 and suggests possible molecular mechanisms by which abnormal insulin signaling may contribute to endothelial dysfunction.

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The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽

10.3390/biom9090476 ◽

2019 ◽

Vol 9 (9) ◽

pp. 476 ◽

Cited By ~ 4

Author(s):

Chia-Jung Li ◽

Pei-Yi Chu ◽

Giou-Teng Yiang ◽

Meng-Yu Wu

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Inhibition Of Proliferation ◽

Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

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Visfatin Induces Inflammation and Insulin Resistance via the NF-κB and STAT3 Signaling Pathways in Hepatocytes

Journal of Diabetes Research ◽

10.1155/2019/4021623 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Yu Jung Heo ◽

Sung-E Choi ◽

Ja Young Jeon ◽

Seung Jin Han ◽

Dae Jung Kim ◽

...

Keyword(s):

Insulin Resistance ◽

Signaling Pathways ◽

Western Blotting ◽

Insulin Signaling ◽

Proinflammatory Cytokine ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

Immunocytochemical Staining ◽

Mrna Levels ◽

Rt Pcr

Background. It has been suggested that visfatin, which is an adipocytokine, exhibits proinflammatory properties and is associated with insulin resistance. Insulin resistance and inflammation are the principal pathogeneses of nonalcoholic fatty liver disease (NAFLD), but the relationship, if any, between visfatin and NAFLD remains unclear. Here, we evaluated the effects of visfatin on hepatic inflammation and insulin resistance in HepG2 cells and examined the molecular mechanisms involved. Methods. After treatment with visfatin, the inflammatory cytokines IL-6, TNF-α, and IL-1β were assessed by real-time polymerase chain reaction (RT-PCR) and immunocytochemical staining in HepG2 cells. To investigate the effects of visfatin on insulin resistance, we evaluated insulin-signaling pathways, such as IR, IRS-1, GSK, and AKT using immunoblotting. We assessed the intracellular signaling molecules including STAT3, NF-κB, IKK, p38, JNK, and ERK by western blotting. We treated HepG2 cells with both visfatin and either AG490 (a JAK2 inhibitor) or Bay 7082 (an NF-κB inhibitor); we examined proinflammatory cytokine mRNA levels using RT-PCR and insulin signaling using western blotting. Results. In HepG2 cells, visfatin significantly increased the levels of proinflammatory cytokines, reduced the levels of proteins (e.g., phospho-IR, phospho-IRS-1 (Tyr612), phospho-AKT, and phospho-GSK-3α/β) involved in insulin signaling, and increased IRS-1 S307 phosphorylation compared to controls. Interestingly, visfatin increased the activities of the JAK2/STAT3 and IKK/NF-κB signaling pathways but not those of the JNK, p38, and ERK pathways. Visfatin-induced inflammation and insulin resistance were regulated by JAK2/STAT3 and IKK/NF-κB signaling; together with AG490 or Bay 7082, visfatin significantly reduced mRNA levels of IL-6, TNF-α and IL-1β and rescued insulin signaling. Conclusion. Visfatin induced proinflammatory cytokine production and inhibited insulin signaling via the STAT3 and NF-κB pathways in HepG2 cells.

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The Main Determinants of Diabetes Mellitus Vascular Complications: Endothelial Dysfunction and Platelet Hyperaggregation

International Journal of Molecular Sciences ◽

10.3390/ijms19102968 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2968 ◽

Cited By ~ 18

Author(s):

Albino Carrizzo ◽

Carmine Izzo ◽

Marco Oliveti ◽

Antonia Alfano ◽

Nicola Virtuoso ◽

...

Keyword(s):

Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Molecular Mechanisms ◽

Vascular Complications ◽

World Health ◽

Northern Europe ◽

Common Disease ◽

Main Determinants ◽

Health Organization ◽

Platelet Hyperaggregation

Diabetes mellitus is a common disease that affects 3–5% of the general population in Italy. In some countries of northern Europe or in North America, it can even affect 6–8% of the population. Of great concern is that the number of cases of diabetes is constantly increasing, probably due to the increase in obesity and the sedentary nature of the population. According to the World Health Organization, in the year 2030 there will be 360 million people with diabetes, compared to 170 million in 2000. This has important repercussions on the lives of patients and their families, and on health systems that offer assistance to patients. In this review, we try to describe in an organized way the pathophysiological continuity between diabetes mellitus, endothelial dysfunction, and platelet hyperaggregation, highlighting the main molecular mechanisms involved and the interconnections.

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Research Status of Differentially Expressed Noncoding RNAs in Type 2 Diabetes Patients

BioMed Research International ◽

10.1155/2020/3816056 ◽

2020 ◽

Vol 2020 ◽

pp. 1-18

Author(s):

Rou Shi ◽

Yingjian Chen ◽

Yuanjun Liao ◽

Rang Li ◽

Chunwen Lin ◽

...

Keyword(s):

Type 2 Diabetes ◽

Signaling Pathways ◽

Insulin Signaling ◽

Target Genes ◽

Mononuclear Cells ◽

Noncoding Rnas ◽

Vascular Complications ◽

Differentially Expressed ◽

Circular Rnas

Aims. Noncoding RNAs (ncRNAs) play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). This paper summarized the current evidences of the involvement microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in the differential expressions and their interaction with each other in T2DM. Methods. The differentially expressed miRNAs, lncRNAs, and circRNAs in the blood circulation (plasma, serum, whole blood, and peripheral blood mononuclear cells) of patients with T2DM were found in PubMed, GCBI, and other databases. The interactions between ncRNAs were predicted based on the MiRWalk and the DIANA Tools databases. The indirect and direct target genes of lncRNAs and circRNAs were predicted based on the starBase V2.0, DIANA Tools, and LncRNA-Target databases. Then, GO and KEGG analysis on all miRNA, lncRNA, and circRNA target genes was performed using the mirPath and Cluster Profile software package in R language. The lncRNA–miRNA and circRNA–miRNA interaction diagram was constructed with Cytoscape. The aim of this investigation was to construct a mechanism diagram of lncRNA involved in the regulation of target genes on insulin signaling pathways and AGE–RAGE signaling pathways of diabetic complications. Results. A total of 317 RNAs, 283 miRNAs, and 20 lncRNAs and circRNAs were found in the circulation of T2DM. Dysregulated microRNAs and lncRNAs were found to be involved in signals related to metabolic disturbances, insulin signaling, and AGE–RAGE signaling in T2DM. In addition, lncRNAs participate in the regulation of key genes in the insulin signaling and AGE–RAGE signaling pathways through microRNAs, which leads to insulin resistance and diabetic vascular complications. Conclusion. Noncoding RNAs participate in the occurrence and development of type 2 diabetes and lead to its vascular complications by regulating different signaling pathways.

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A mathematical model of metabolic insulin signaling pathways

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00571.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. E1084-E1101 ◽

Cited By ~ 124

Author(s):

Ahmad R. Sedaghat ◽

Arthur Sherman ◽

Michael J. Quon

Keyword(s):

Experimental Data ◽

Mathematical Model ◽

Insulin Receptor ◽

Signaling Pathways ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Insulin Dose ◽

Model Parameters ◽

Insight Into

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-ζ is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.

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Molecular Mechanisms of Endothelial Dysfunction in the Insulin-Resistant State: the Roles of Abnormal Pteridine Metabolism

Pteridines ◽

10.1515/pteridines.2003.14.1.13 ◽

2003 ◽

Vol 14 (1) ◽

pp. 13-16

Author(s):

Kazuya Shinozaki ◽

Atsunori Kashiwagi ◽

Masahiro Masada ◽

Tomio Okamura

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Molecular Mechanisms ◽

No Synthase ◽

Oral Supplementation ◽

Insulin Resistant ◽

Underlying Mechanisms ◽

Vascular Oxidative Stress ◽

Resistant State ◽

Insulin Resistant State

Abstract Although abnormalities in endothelial function are described in various insulin-resistant conditions, including obesity, diabetes, and hypertension in both humans and animal models, the underlying mechanisms are poorly understood. Experimental evidence suggests that (6R)-5,6,7,8-tetrahydrobiopterin (BH4), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS bat also in Controlling the formation of superoxide anion (O2 ) in endothelial cells. Under insulin-resistant conditions where BH4 levels are suboptimal, the production of O2 by NO synthase leads to endothelial dysfunction. Furthermore, oral supplementation of BH4 (10 mg/kg/day) for 8 weeks restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of eNOS in the aorta of insulin-resistant rats. These results suggest that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin-resistant State.

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Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance

Reproduction ◽

10.1530/rep-08-0161 ◽

2008 ◽

Vol 136 (3) ◽

pp. 335-344 ◽

Cited By ~ 24

Author(s):

Erica Louden ◽

Maggie M Chi ◽

Kelle H Moley

Keyword(s):

Insulin Resistance ◽

Signaling Pathways ◽

Insulin Signaling ◽

Kinase Activity ◽

Pi3 Kinase ◽

Ampk Activation ◽

Embryonic Cells ◽

Insulin Resistant

Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

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Abstract 649: Endothelial-derived Sphingolipids Preserve Systemic Vascular Function And Blood Pressure

Hypertension ◽

10.1161/hyp.64.suppl_1.649 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Anna Cantalupo ◽

Yi Zhang ◽

Hideru Obinata ◽

Syvain Galvain ◽

Xiang-Cheng Jiang ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Molecular Mechanisms ◽

De Novo ◽

Critical Event ◽

Ang Ii ◽

Serine Palmitoyltransferase ◽

Induced Hypertension

Endothelial dysfunction is a critical event in many cardiovascular diseases including hypertension. Although lipid signaling is implicated in endothelial dysfunction and cardiovascular diseases, specific molecular mechanisms are poorly understood. Here we report a novel regulation of endothelial sphingolipid synthesis by Nogo-B, membrane protein of the endoplasmic reticulum that modulates local sphingolipid production with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, rate-limiting enzyme of the sphingolipid de novo synthesis, controlling endothelial sphingosine 1-phosphate production and its autocrine G-protein-coupled receptor-dependent signaling actions. Mice lacking Nogo-B are hypotensive (90.1±1.6 vs. 119.9±2.6 mmHg WT mice), resistant to Ang-II (500ng/Kg/min)-induced hypertension (150.4±2.5 vs. 108.4±1.5 mmHg, compared to WT mice, 24 days after AngII infusion), and preserve endothelial function and nitric oxide release. Pharmacological inhibition of serine palmitoyltransferase with myriocin in mice that lack Nogo-B reinstated endothelial dysfunction and Ang-II-induced hypertension (143.9±1.5 vs. 90.1±1.6 mmHg, myriocin vs. vehicle treated Nogo-A/B-/- mice). Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and indicates that autocrine sphingolipids signaling within the endothelium are critical for vascular function and blood pressure homeostasis.

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Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive and Akt-dependent pathways

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00285.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. H1851-H1860 ◽

Cited By ~ 6

Author(s):

Karla Bianca Neves ◽

Aurelie Nguyen Dinh Cat ◽

Rheure Alves-Lopes ◽

Katie Yates Harvey ◽

Rafael Menezes da Costa ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Insulin Signaling ◽

Vascular Function ◽

Glucose Transporter ◽

Critical Role ◽

Vascular Complications ◽

Mesenteric Arteries ◽

Nitric Oxide Signaling ◽

Vascular Oxidative Stress

Chemerin and its G protein-coupled receptor [chemerin receptor 23 (ChemR23)] have been associated with endothelial dysfunction, inflammation, and insulin resistance. However, the role of chemerin on insulin signaling in the vasculature is still unknown. We aimed to determine whether chemerin reduces vascular insulin signaling and whether there is interplay between chemerin/ChemR23, insulin resistance, and vascular complications associated with type 2 diabetes (T2D). Molecular and vascular mechanisms were probed in mesenteric arteries and cultured vascular smooth muscle cells (VSMCs) from C57BL/6J, nondiabetic lean db/m, and diabetic obese db/db mice as well as in human microvascular endothelial cells (HMECs). Chemerin decreased insulin-induced vasodilatation in C57BL/6J mice, an effect prevented by CCX832 (ChemR23 antagonist) treatment. In VSMCs, chemerin, via oxidative stress- and ChemR23-dependent mechanisms, decreased insulin-induced Akt phosphorylation, glucose transporter 4 translocation to the membrane, and glucose uptake. In HMECs, chemerin decreased insulin-activated nitric oxide signaling. AMP-activated protein kinase phosphorylation was reduced by chemerin in both HMECs and VSMCs. CCX832 treatment of db/db mice decreased body weight, insulin, and glucose levels as well as vascular oxidative stress. CCX832 also partially restored vascular insulin responses in db/db and high-fat diet-fed mice. Our novel in vivo findings highlight chemerin/ChemR23 as a promising therapeutic target to limit insulin resistance and vascular complications associated with obesity-related diabetes. NEW & NOTEWORTHY Our novel findings show that the chemerin/chemerin receptor 23 axis plays a critical role in diabetes-associated vascular oxidative stress and altered insulin signaling. Targeting chemerin/chemerin receptor 23 may be an attractive strategy to improve insulin signaling and vascular function in obesity-associated diabetes.

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The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

International Journal of Molecular Sciences ◽

10.3390/ijms21239309 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9309

Author(s):

Jessica Maiuolo ◽

Rocco Mollace ◽

Micaela Gliozzi ◽

Vincenzo Musolino ◽

Cristina Carresi ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Endothelial Dysfunction ◽

Blood Vessels ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Vascular Complications ◽

Therapeutic Interventions ◽

The Impact

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

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