Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP

2005 ◽  
Vol 289 (1) ◽  
pp. H206-H211 ◽  
Author(s):  
Hong Ding ◽  
Andrew G. Howarth ◽  
Malarvannan Pannirselvam ◽  
Todd J. Anderson ◽  
David L. Severson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Microvascular Disease ◽  
Mesenteric Arteries ◽  
Mrna Levels ◽  
Important Indicator ◽  
Membrane Function

The Type 2 diabetic db/ db mouse experiences vascular dysfunction typified by changes in the contraction and relaxation profiles of small mesenteric arteries (SMAs). Contractions of SMAs from the db/ db mouse to the α1-adrenoceptor agonist phenylephrine (PE) were significantly enhanced, and acetylcholine (ACh)-induced relaxations were significantly depressed. Drug treatment of db/ db mice with a nonthiazolidinedione peroxisome prolifetor-activated receptor-γ agonist and insulin sensitizing agent 2-[2-(4-phenoxy-2-propylphenoxy)ethyl]indole-5-acetic acid (COOH) completely prevented the changes in endothelium-dependent relaxation, but, with the discontinuation of therapy, endothelial dysfunction returned. Dysfunctional SMAs were found to specifically upregulate the expression of a 35-kDa isoform of sarcolemmal membrane-associated protein (SLMAP), which is a component of the excitation-contraction coupling apparatus and implicated in the regulation of membrane function in muscle cells. Real-time PCR revealed high SLMAP mRNA levels in the db/ db microvasculature, which were markedly downregulated during COOH treatment but elevated again when drug therapy was discontinued. These data reveal that the microvasculature in db/ db mice undergoes significant changes in vascular function with the endothelial component of vascular dysfunction specifically correlating with the overexpression of SLMAP. Thus changes in SLMAP expression may be an important indicator for microvascular disease associated with Type 2 diabetes.

scholarly journals Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes

2008 ◽  
Vol 294 (6) ◽  
pp. H2743-H2749 ◽  
Author(s):  
Kamakshi Sachidanandam ◽  
Mostafa M. Elgebaly ◽  
Alex K. Harris ◽  
Jim R. Hutchinson ◽  
Erin M. Mezzetti ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Receptor Antagonism ◽  
Potent Vasoconstrictor ◽  
The Individual ◽  
The Right ◽  
And Control

Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg·kg−1·day−1) or type B (ETB; A-192621; 15 or 30 mg·kg−1·day−1) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

scholarly journals An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model

2020 ◽  
Vol 45 (4) ◽  
pp. 397-404
Author(s):  
Tugba Gurpinar Çavuşoğlu ◽  
Ertan Darıverenli ◽  
Kamil Vural ◽  
Nuran Ekerbicer ◽  
Cevval Ulman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Fasting Blood Glucose ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Insulin Levels ◽  
Type 2 Diabetic

AbstractObjectivesType 2 diabetes is a common metabolic disease and anxiety disorders are very common among diabetics. Buspirone is used in the treatment of anxiety, also having blood glucose-lowering effects. The aim of the study was to investigate the effects of buspirone on the glucose and lipid metabolism as well as vascular function in type 2 diabetic rats.MethodsA type 2-diabetic model was induced through a high-fat diet for eight weeks followed by the administration of low-dose streptozotocin (35 mg/kg, intraperitoneal) in rats. Buspirone was given at two different doses (1.5 mg/kg/d and 5 mg/kg/d) and combined with metformin (300 mg/kg/d). The fasting glucose and insulin levels, lipid profile were analyzed, and vascular response measured from the thoracic aorta was also evaluated.ResultsBoth doses of buspirone caused a significant improvement in fasting blood glucose levels. In particular, the buspirone treatment, combined with metformin, improved endothelial dysfunction and was found to be correlated with decreased nitrate/nitrite levels.ConclusionsBuspirone may be effective in the treatment of type 2 diabetes, either alone or in combination with other treatments, particularly in terms of endothelial dysfunction, inflammation and impaired blood glucose, and insulin levels.

scholarly journals Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction

2018 ◽  
Vol 19 (12) ◽  
pp. 3942 ◽  
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Jiangning Yang ◽  
Claes-Göran Östenson ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Mesenteric Arteries ◽  
Vascular Contraction ◽  
Gk Rats ◽  
Vasoconstrictor Response

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.

scholarly journals Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

2019 ◽  
Vol 20 (15) ◽  
pp. 3775 ◽  
Author(s):  
Cesar A. Meza ◽  
Justin D. La Favor ◽  
Do-Houn Kim ◽  
Robert C. Hickner
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Blood Flow ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

Abstract P632: Nlrp3/inflammasome Activation Contributes To Aldosterone-induced Vascular Dysfunction In Type 2 Diabetes.

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nathanne S Ferreira ◽  
Thiago Bruder-Nascimento ◽  
Camila A Pereira ◽  
Camila Z Zanotto ◽  
Douglas S Prado ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Diabetic Patients ◽  
Inflammasome Activation ◽  
Caspase 1

Diabetic patients and animal models of type 2 diabetes (DM2) display increased plasma aldosterone (aldo) levels. Aldo induces vascular inflammation and endothelial dysfunction. NOD-like receptors, which are pattern recognition receptors involved in a variety of host innate immune responses, promote vascular inflammation. We hypothesized that aldo via mineralocorticoid receptors (MR) activates the inflammasome platform in the vasculature of DM2 mice. Control (db/+) and diabetic (db/db) mice were treated with vehicle or spironolactone (spiro - MR antagonist, 50 mg/Kg/day). Mesenteric resistance arteries (MA) from db/db mice exhibited reduced acetylcholine (ACh) dilation, which was reversed by spiro [Emax (% of relaxation): db/+: 78.5±4.1; db/db: 40.5±6.4; db/+spiro: 77.0±3.8; db/db+spiro: 62.8±5.9 n=3-6 p<0.05]. Spiro treatment reduced caspase-1 and mature IL-1β content in MA from db/db mice. Spiro also reduced caspase-1 activity in macrophages from peritoneal lavage of db/db mice [% of activity: db/+: 33.9±2.5; db/db: 51.8±7.4; db/+spiro: 31.1±1.9; db/db+spiro: 34.8±3.8 n=4-7, p<0.05]. In vitro, aldo increased mature IL-1β in vascular smooth muscle cells (VSMC) (cont: 0.9±0.01 ; LPS+Nigericine: 6.1±2.1 ; Aldo 4h: 9.7±2.6; LPS+Aldo 4h: 12.8±1.9 n=3-5, p<0.05). To determine whether aldo in vivo directly activates NLRP3/inflammasome in the vasculature and whether NLRP3 activation contributes to aldo-induced vascular injury, aldo was infused (600 ug/Kg/day for 14 days) in wild type (WT) and NLRP3 knockout mice ( NLRP3-/- ) after bone marrow transplantation from WT donor. The groups were constituted: WT->WT, WT->WT+aldo and WT-> NLRP3 -/-+aldo. NLRP3 -/- mice were protected against aldo-induced endothelial dysfunction [Emax: WT: 89.3±2.9; WT+aldo: 39.8±1.8; NLRP3-/- +aldo: 87.7±4.2, p<0.05]. Aldo treatment leaded to endothelial dysfunction in WT ->WT mice, but WT-> NLRP3 -/- mice were protected from aldo-induced endothelial dysfunction [Emax: WT->WT: 95.1±3.1; WT->WT+aldo: 57.1±4.7; WT->NLRP3-/-+aldo: 85.3±3.1 p<0.05]. These results suggest that NLRP3/inflammasome in the vasculature plays a crucial role on aldo/MR-induced vascular damage and on DM2-associated vascular dysfunction. Financial Support: FAPESP, CAPES, CNPq.

Abstract 211: The DPP-4 Inhibitor Linagliptan Reverses Endothelial Dysfunction of Mesenteric Arteries From Rats Fed a Western Diet

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Salheen M Salheen ◽  
Jason C Nguyen ◽  
Trisha A Jenkins ◽  
Owen L Woodman
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Western Diet ◽  
Mesenteric Arteries ◽  
Standard Diet ◽  
High Fat ◽  
Total Fat ◽  
Endothelium Dependent Relaxation ◽  
Superoxide Release

A high-fat ‘western’ diet (WD), a risk factor for the development of type 2 diabetes, may cause endothelial dysfunction one of the earliest events in atherogenesis. The dipeptidyl peptidase-4 (DPP-4) inhibitors are used to lower hyperglycemia in type 2 diabetes which is also associated with endothelial dysfunction. We tested whether consumption of a WD affected endothelium-dependent relaxation (EDR) of rat mesenteric arteries (MA) and whether the DPP-4 inhibitor linagliptin (1μM) improves EDR. Wistar Hooded rats were fed a standard diet (SD, 7% total fat) or WD (21% total fat) for 10 weeks. Consumption of the WD significantly increased superoxide release from MA assayed by lucigenin chemiluminescence (WD 1210±180 counts/mg versus SD 543±156 counts/mg, n=7-8, p<0.05) and linagliptin significantly reduced the vascular superoxide release (WD+linagliptin 432±102 counts/mg, p<0.05). Acetylcholine (ACh)-induced endothelium-dependent relaxation of MA was assessed using wire myography. WD significantly reduced the sensitivity to ACh (pEC50, SD 7.72±0.08, WD, 7.32±0.05 n=8, p<0.05) and treatment with linagliptin improved endothelial function (ACh pEC50 WD+linagliptin, 7.74±0.12, n=8, p<0.05). The contribution of EDHF to ACh-induced relaxation was determined in the presence of L-NNA and ODQ to block NOS and guanylate cyclase. EDHF-mediated relaxation was improved by linagliptin (pEC50, WD 6.24±0.06, WD+linagliptin 6.95±0.12, n=4-5, p<0.05). Linagliptin also significantly improved the contribution of NO (determined in the presence of TRAM-34 + apamin to block IKCa and SKCa) to relaxation (pEC50, WD 6.50±0.13, WD+linagliptin 7.30±0.10 n=4-6, p<0.05). Linagliptin significantly reduced vascular superoxide levels and improved the contribution of both NO and EDHF to preserve endothelium-dependent relaxation in rats fed a high fat diet. DPP-4 inhibition may have effects in addition to the lowering of plasma glucose to improve vascular function in diabetes.

scholarly journals Cardiovascular Benefits of GLP-1-BasedTherapies in Patients with Diabetes Mellitus Type 2: Effects on Endothelial and Vascular Dysfunction beyond Glycemic Control

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Thomas Forst ◽  
Matthias M. Weber ◽  
Andreas Pfützner
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Vascular Function ◽  
Current Knowledge ◽  
Vascular Dysfunction ◽  
Cardiovascular Effects ◽  
Glucagon Secretion ◽  
Receptor Agonists ◽  
Dpp Iv

Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease accompanied by vascular dysfunction and a tremendous increase in cardiovascular mortality. Numerous adipose-tissue-derived factors and beta cell dysfunction contribute to the increased cardiovascular risk in patients with T2DM. Nowadays, numerous pharmacological interventions are available to lower blood glucose levels in patients with type 2 diabetes. Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality. Recently, incretin-based therapies (GLP-1 receptor agonists and DPP-IV inhibitors) have been introduced in the treatment of T2DM. Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies. The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors.

scholarly journals Effects of Atorvastatin and Insulin in Vascular Dysfunction Associated With Type 2 Diabetes

2014 ◽  
pp. 189-197 ◽  
Author(s):  
C. M. SENA ◽  
P. MATAFOME ◽  
T. LOURO ◽  
E. NUNES ◽  
R. M. SEIÇA
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Lipid Peroxides ◽  
Metabolic Parameters ◽  
Carbonyl Stress ◽  
Gk Rats

Atorvastatin and insulin have distinct mechanisms of action to improve endothelial function. Therefore, we hypothesized that atorvastatin and insulin therapies alone or in combination could have beneficial effects on endothelium-dependent vascular reactivity, oxidative stress, inflammation and metabolic parameters in Goto-Kakizaki (GK) rats, a model of type 2 diabetes fed with atherogenic diet (GKAD). In parallel with the development of diabetes and lipid profile, the generation of oxidative stress was determined by measurement of lipid peroxides and oxidized proteins and the presence of inflammation was evaluated by assessing C-reactive protein (CRP). Additionally, endothelial dependent and independent vascular sensitivity to acetylcholine and sodium nitroprusside were evaluated. GKAD showed increased carbonyl stress, inflammation, fasting glycemia, dyslipidemia and endothelial dysfunction when compared to control GK rats. Noteworthy, supplementation with insulin deteriorated endothelial dysfunction while atorvastatin induced an improvement. Atorvastatin and insulin therapies in combination improved metabolic parameters, CRP levels and insulin resistance indexes and ameliorated endothelial dysfunction in GKAD rats while they were unable to reduce urinary 8-isoprostranes and plasma carbonyl compounds. The therapeutic association of atorvastatin and insulin provided a better metabolic control with a reduction in endothelial dysfunction in GKAD rats by a mechanism that involves an improvement in systemic inflammation.

scholarly journals Relationship between Indices of Vascular Function and Presence of Overt Cardiovascular Disease among Persons with Poorly Controlled Type 2 Diabetes

2021 ◽  
Vol 8 (12) ◽  
pp. 185
Author(s):  
Sofia Antoniou ◽  
Katerina K. Naka ◽  
Marios Papadakis ◽  
Aris Bechlioulis ◽  
Dimitrios Makriyiannis ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Glycemic Control ◽  
Vascular Function ◽  
Disease Duration ◽  
Vascular Dysfunction ◽  
Macrovascular Disease ◽  
Group 2 ◽  
Group 1

The aim of this study was to assess the factors associated with impaired vascular function in patients with poorly controlled type 2 diabetes (DM2) with and without overt cardiovascular disease (CVD). Ninety-five patients with DM2 and poor glycemic control were recruited and divided into two groups: Group 1, with known CVD (n = 38), and Group 2, without CVD (n = 57). Patients in Group 2 were further subdivided into those with short (<5 years, group 2b) and long (>5 years, group 2a) diabetes duration. Subclinical markers of atherosclerosis were assessed. Glycemic control was similar in the two groups (HbA1c: 9.2% (1.5) vs. 9.4% (1.8), p = 0.44). In Group 1, lower FMD (3.13 (2.16)% vs. 4.7 (3.4)%, p < 0.05) and higher cIMT (1.09 (0.3) mm vs. 0.96 (0.2) mm, p < 0.05) was seen compared with Group 2, whereas PWV was similar (12.1 (3.4) vs. 11.3 (3.0) m/s, p = 0.10). Patients in Group 2b had significantly lower PWV and cIMT and higher FMD compared to Group 1 (p < 0.05). Among patients with poorly controlled T2D, more pronounced vascular dysfunction was present in those with overt macrovascular disease. In patients with T2D without known CVD, vascular dysfunction was associated with disease duration. The use of vascular indices for cardiovascular risk stratification in patients with T2D requires further study.

scholarly journals The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

2020 ◽  
Vol 2 (1) ◽  
pp. H19-H28 ◽  
Author(s):  
Sarah Costantino ◽  
Shafeeq A Mohammed ◽  
Samuele Ambrosini ◽  
Francesco Paneni
Keyword(s):  
Type 2 Diabetes ◽  
Vascular Function ◽  
Current Knowledge ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Epigenetic Modifications ◽  
Individual Risk ◽  
Limited Information ◽  
Obesity And Diabetes

Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the ‘epigenetic landscape’ in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.

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