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

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.

Download Full-text

P735Interleukin-33 induced eosinophilia restores perivascular adipose tissue function in obesity

European Heart Journal ◽

10.1093/eurheartj/ehz747.0339 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Saxton ◽

R J Potter ◽

S B Withers ◽

R Grencis ◽

A M Heagerty

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Plasma Insulin ◽

Vascular Tone ◽

Mesenteric Arteries ◽

Obese Mice ◽

High Fat ◽

Perivascular Adipose Tissue

Abstract Background/Purpose Perivascular adipose tissue (PVAT) is essential in the modulation of vascular tone. Recently we have shown that resident eosinophils play a vital role in regulating PVAT function. In obesity, eosinophil numbers are reduced and PVAT anticontractile function is lost, resulting in increased vascular tone, which will contribute to development of hypertension and type-2 diabetes. Evidence suggests that eosinophilia resulting from parasitic infection may be useful in improving glucose tolerance; therefore, we investigated the effects of eosinophilia on PVAT function in health and obesity. Methods Control mice and a high fat fed mouse model of obesity were administered intraperitoneal injections of interleukin-33 (IL-33, 0.1μg) over a five day period. Blood pressure, blood glucose and plasma insulin were measured and compared with un-injected control and obese mice. Wire myography was used to assess the vascular contractility of mesenteric arteries (<250μm, +/− PVAT) from both injected and un-injected control and obese mice in response to noradrenaline. ELISAs and immunohistochemistry were used to examine eosinophil numbers. Results High fat feeding induced significant elevations in blood pressure, blood glucose and plasma insulin, which were reduced using IL-33 injections. Eosinophilia was confirmed in blood plasma using an eosinophil cationic protein ELISA. Using wire myography, mesenteric arteries from control mice PVAT exerted an anticontractile effect on the vessels, which was enhanced in control mice injected with IL-33. In obese mice, the PVAT anticontractile effect was lost, but was restored in IL-33 injected obese mice. Using immunohistochemistry, we confirm that eosinophils numbers in PVAT were reduced in obesity and increased in IL-33 treated PVAT. Conclusions IL-33 injections induced eosinophilia in both control and obese mice. IL-33 treatment restored PVAT function in obesity, and enhanced the anticontractile function of PVAT in healthy animals. In addition, only five consecutive injections of IL-33 reversed development of hypertension and type-2 diabetes in obese mice. These data suggest that IL-33 induced eosinophilia presents a novel approach to treatment of hypertension and type-2 diabetes in obesity. Acknowledgement/Funding British Heart Foundation

Download Full-text

Decrease of postprandial endothelial dysfunction by spice mix added to high‐fat hamburger meat in men with Type 2 diabetes mellitus

Diabetic Medicine ◽

10.1111/dme.12120 ◽

2013 ◽

Vol 30 (5) ◽

pp. 590-595 ◽

Cited By ~ 18

Author(s):

Z. Li ◽

S. M. Henning ◽

Y. Zhang ◽

N. Rahnama ◽

A. Zerlin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Endothelial Dysfunction ◽

High Fat

Download Full-text

Type 2 diabetes: increased expression and contribution of IKCa channels to vasodilation in small mesenteric arteries of ZDF rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00240.2013 ◽

2014 ◽

Vol 307 (8) ◽

pp. H1093-H1102 ◽

Cited By ~ 20

Author(s):

Christian Schach ◽

Markus Resch ◽

Peter M. Schmid ◽

Guenter A. Riegger ◽

Dierk H. Endemann

Keyword(s):

Type 2 Diabetes ◽

Protein Expression ◽

Experimental Models ◽

Diabetic Rats ◽

Mesenteric Arteries ◽

Rt Pcr ◽

Mrna And Protein Expression ◽

Zdf Rats ◽

Endothelium Dependent Relaxation

Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the experimental models in our study. Third-order mesenteric arteries were dissected and mounted on a pressure myograph; mRNA was quantified by RT-PCR and channel proteins by Western blotting. Under nitric oxide (NO) synthase and cyclooxygenase inhibition, endothelial stimulation with ACh fully relaxes control but not diabetic arteries. In contrast, when small-conductance calcium-activated potassium (KCa) channels and intermediate- and large-conductance KCa (I/BKCa) are inhibited with apamin and charybdotoxin, NO is able to compensate for ACh-induced relaxation in control but not in diabetic vessels. After replacement of charybdotoxin with 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; IKCa inhibitor), ACh-induced relaxation in diabetic animals is attenuated. Specific inhibition with TRAM-34 or charybdotoxin attenuates ACh relaxation in diabetes. Stimulation with 1-ethyl-2-benzimidazolinone (IKCa activator) shows a reduced relaxation in diabetes. Activation of BKCa with 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one NS619 leads to similar relaxations of control and diabetic arteries. RT-PCR and Western blot analysis demonstrate elevated mRNA and protein expression levels of IKCa in diabetes. Our results suggest that the compensatory effect of NO and EDH-associated, endothelium-dependent relaxation is reduced in ZDF rats. Specific blockade of IKCa with TRAM-34 reduces NO and EDH-type relaxation in diabetic rats, indicating an elevated contribution of IKCa in diabetic small mesenteric artery relaxation. This finding correlates with increased IKCa mRNA and protein expression in this vessel.

Download Full-text

Type 2 diabetes progression differently affects endothelial function and vascular contractility in the aorta and the pulmonary artery

Scientific Reports ◽

10.1038/s41598-021-85606-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bernardete F. Melo ◽

Jesus Prieto-Lloret ◽

Marlene D. Cabral ◽

Fatima O. Martins ◽

Inês B. Martins ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Pulmonary Artery ◽

Endothelial Function ◽

Pulmonary Disease ◽

Systemic Circulation ◽

Diabetic Rats ◽

High Fat ◽

Vascular Contractility

AbstractType 2 diabetes (T2D) is associated with cardiovascular and pulmonary disease. How T2D affects pulmonary endothelial function is not well characterized. We investigated the effects of T2D progression on contractility machinery and endothelial function in the pulmonary and systemic circulation and the mechanisms promoting the dysfunction, using pulmonary artery (PA) and aorta. A high-fat (HF, 3 weeks 60% lipid-rich diet) and a high-fat/high-sucrose (HFHSu, combined 60% lipid-rich diet and 35% sucrose during 25 weeks) groups were used as prediabetes and T2D rat models. We found that T2D progression differently affects endothelial function and vascular contractility in the aorta and PA, with the contractile machinery being altered in the PA and aorta in prediabetes and T2D animals; and endothelial function being affected in both models in the aorta but only affected in the PA of T2D animals, meaning that PA is more resistant than aorta to endothelial dysfunction. Additionally, PA and systemic endothelial dysfunction in diabetic rats were associated with alterations in the nitrergic system and inflammatory pathways. PA dysfunction in T2D involves endothelial wall mineralization. The understanding of the mechanisms behind PA dysfunction in T2D can lead to significant advances in both preventative and therapeutic treatments of pulmonary disease-associated diabetes.

Download Full-text

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00037.2005 ◽

2005 ◽

Vol 289 (1) ◽

pp. H206-H211 ◽

Cited By ~ 16

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.

Download Full-text

Erythrocytes Induce Endothelial Injury in Type 2 Diabetes Through Alteration of Vascular Purinergic Signaling

Frontiers in Pharmacology ◽

10.3389/fphar.2020.603226 ◽

2020 ◽

Vol 11 ◽

Author(s):

Ali Mahdi ◽

Yahor Tratsiakovich ◽

John Tengbom ◽

Tong Jiao ◽

Lara Garib ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Ex Vivo ◽

Purinergic Receptor ◽

Purinergic Signaling ◽

Vascular Dysfunction ◽

Endothelium Dependent Relaxation ◽

Human Rbcs

It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h ex vivo co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after in vivo transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects ex vivo, and in aortas of healthy rats after transfusion with GK RBCs in vivo. The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X7R but not P2Y6R antagonism. Transfusion with GK RBCs in vivo impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X7R but not P2Y6R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X7R but not P2Y6R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D.

Download Full-text

Endothelial dysfunction in small arteries and early signs of atherosclerosis in ApoE knockout rats

Scientific Reports ◽

10.1038/s41598-020-72338-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Simin Berenji Ardestani ◽

Ingrid Eftedal ◽

Michael Pedersen ◽

Per Bendix Jeppesen ◽

Rikke Nørregaard ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Early Stage ◽

Western Diet ◽

Mesenteric Arteries ◽

Standard Diet ◽

Resistance Arteries ◽

Small Resistance ◽

Apoe Ko

Abstract Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20–24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development.

Download Full-text

Exercise Affects Blood Glucose Levels and Tissue Chromium Distribution in High-Fat Diet-Fed C57BL6 Mice

Molecules ◽

10.3390/molecules25071658 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1658 ◽

Cited By ~ 2

Author(s):

Geng-Ruei Chang ◽

Po-Hsun Hou ◽

Wen-Kai Chen ◽

Chien-Teng Lin ◽

Hsiao-Pei Tsai ◽

...

Keyword(s):

Type 2 Diabetes ◽

High Fat Diet ◽

Cell Function ◽

Body Weight Gain ◽

Liver Fat ◽

Standard Diet ◽

Model Assessment ◽

Obese Mice ◽

High Fat

Obesity is commonly associated with hyperglycemia and type 2 diabetes and negatively affects chromium accumulation in tissues. Exercise prevents and controls obesity and type 2 diabetes. However, little information is available regarding chromium changes for regulating glucose homeostasis in high-fat diet (HFD)-fed animals/humans who exercise. Therefore, this study explored the effects of exercise and whether it alters chromium distribution in obese mice. Male C57BL6/J mice aged 4 weeks were randomly divided into two groups and fed either an HFD or standard diet (SD). Each group was subgrouped into two additional groups in which one subgroup was exposed to treadmill exercise for 12 weeks and the other comprised control mice. HFD-fed mice that exercised exhibited significant lower body weight gain, food/energy intake, daily food efficiency, and serum leptin and insulin levels than did HFD-fed control mice. Moreover, exercise reduced fasting glucose and enhanced insulin sensitivity and pancreatic β-cell function, as determined by homeostasis model assessment (HOMA)-insulin resistance and HOMA-β indices, respectively. Exercise also resulted in markedly higher chromium levels within the muscle, liver, fat tissues, and kidney but lower chromium levels in the bone and bloodstream in obese mice than in control mice. However, these changes were not noteworthy in SD-fed mice that exercised. Thus, exercise prevents and controls HFD-induced obesity and may modulate chromium distribution in insulin target tissues.

Download Full-text

GLP-1 Agonists Liraglutide Improved Vascular Endothelial Function in Type 2 Diabetes Rats

10.36502/2020/droa.6168 ◽

2020 ◽

Vol 2 (2) ◽

pp. 46-55

Author(s):

Li X ◽

Wu W ◽

Wang Y ◽

Zhang X ◽

Feng X ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Mesenteric Arteries ◽

Vascular Endothelial ◽

Vascular Endothelial Dysfunction ◽

Vascular Endothelial Function

Objective: Liraglutide (LIRA), a Glucagon-like peptide-1 (GLP-1) receptor agonist, showed potential vascular protective effects with the mechanism remained incompletely understood. Therefore, this study aimed to investigate whether LIRA exerts its effect on vascular endothelial function in rats with type 2 diabetes mellitus (T2DM) via caveolin-1/ endothelial oxide synthase (eNOS) expression. Methods: T2DM rats were used as study subjects and randomly divided into four groups: 1) Veh group, 2) Veh+LIRA group, 3) T2DM group, and 4) T2DM+LIRA group. All rats received either saline or LIRA 0.2 mg/kg (by i.p. injection) per day for 4 weeks. After the model was successfully established, vascular endothelial function was determined the effect of vasodilator to mesenteric artery rings. Immunofluorescence and western blot were performed to understand the molecular mechanism. Cultured HUVECs with small interfering RNA (siRNA) under high glucose (HG), NO concentration, and western blot were performed to understand the molecular mechanism between LIRA and vascular endothelial function. Results: Based on our results, the LIRA reduced hyperglycemia and ameliorated vascular endothelial dysfunction in type 2 diabetic mice. LIRA activated eNOS phosphorylation, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of mesenteric arteries. Besides, from its anti-oxidative capacity, LIRA activated eNOS to dilate the mesenteric arteries via the downregulation of Cav-1. Conclusion: LIRA ameliorates vascular endothelial dysfunction in rats with type 2 diabetes mellitus via anti-oxidative and activated eNOS by downregulated Cav-1.

Download Full-text