Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes

2015 ◽  
Vol 93 (7) ◽  
pp. 555-561 ◽  
Author(s):  
Adrian Sturza ◽  
Oana M. Duicu ◽  
Adrian Vaduva ◽  
Maria D. Dănilă ◽  
Lavinia Noveanu ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Rat Model ◽  
Experimental Diabetes ◽  
Xylenol Orange ◽  
Diabetic Rat ◽  
Organ Bath ◽  
Monoamine Oxidases ◽  
Mao B ◽  
Cardiovascular Morbidity And Mortality ◽  
Endothelium Dependent Relaxation

Diabetes mellitus (DM) is widely recognized as the most severe metabolic disease associated with increased cardiovascular morbidity and mortality. The generation of reactive oxygen species (ROS) is a major event causally linked to the development of cardiovascular complications throughout the evolution of DM. Recently, monoamine oxidases (MAOs) at the outer mitochondrial membrane, with 2 isoforms, MAO-A and MAO-B, have emerged as novel sources of constant hydrogen peroxide (H2O2) production in the cardiovascular system via the oxidative deamination of biogenic amines and neurotransmitters. Whether MAOs are mediators of endothelial dysfunction in DM is unknown, and so we studied this in a streptozotocin-induced rat model of diabetes. MAO expression (mRNA and protein) was increased in both arterial samples and hearts isolated from the diabetic animals. Also, H2O2 production (ferrous oxidation – xylenol orange assay) in aortic samples was significantly increased, together with an impairment of endothelium-dependent relaxation (organ-bath studies). MAO inhibitors (clorgyline and selegiline) attenuated ROS production by 50% and partially normalized the endothelium-dependent relaxation in diseased vessels. In conclusion, MAOs, in particular the MAO-B isoform, are induced in aortas and hearts in the streptozotocin-induced diabetic rat model and contribute, via the generation of H2O2, to the endothelial dysfunction associated with experimental diabetes.

scholarly journals Diabetes Attenuates the Contribution of Endogenous Nitric Oxide but Not Nitroxyl to Endothelium Dependent Relaxation of Rat Carotid Arteries

2021 ◽  
Vol 11 ◽  
Author(s):  
Jasmin Chendi Li ◽  
Anida Velagic ◽  
Cheng Xue Qin ◽  
Mandy Li ◽  
Chen Huei Leo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitrogen Oxide ◽  
Carotid Arteries ◽  
Body Weight Gain ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Endothelium Dependent Relaxation

Introduction:Endothelial dysfunction is a major risk factor for several of the vascular complications of diabetes, including ischemic stroke. Nitroxyl (HNO), the one electron reduced and protonated form of nitric oxide (NO•), is resistant to scavenging by superoxide, but the role of HNO in diabetes mellitus associated endothelial dysfunction in the carotid artery remains unknown.Aim: To assess how diabetes affects the role of endogenous NO• and HNO in endothelium-dependent relaxation in rat isolated carotid arteries.Methods: Male Sprague Dawley rats were fed a high-fat-diet (HFD) for 2 weeks prior to administration of low dose streptozotocin (STZ; 35 mg/kg i. p./day) for 2 days. The HFD was continued for a further 12 weeks. Sham rats were fed standard chow and administered with citrate vehicle. After 14 weeks total, rats were anesthetized and carotid arteries collected to assess responses to the endothelium-dependent vasodilator, acetylcholine (ACh) by myography. The combination of calcium-activated potassium channel blockers, TRAM-34 (1 μmol/L) and apamin (1 μmol/L) was used to assess the contribution of endothelium-dependent hyperpolarization to relaxation. The corresponding contribution of NOS-derived nitrogen oxide species to relaxation was assessed using the combination of the NO• synthase inhibitor, L-NAME (200 μmol/L) and the soluble guanylate cyclase inhibitor ODQ (10 μmol/L). Lastly, L-cysteine (3 mmol/L), a selective HNO scavenger, and hydroxocobalamin (HXC; 100 μmol/L), a NO• scavenger, were used to distinguish between NO• and HNO-mediated relaxation.Results: At study end, diabetic rats exhibited significantly retarded body weight gain and elevated blood glucose levels compared to sham rats. The sensitivity and the maximal relaxation response to ACh was significantly impaired in carotid arteries from diabetic rats, indicating endothelial dysfunction. The vasorelaxation evoked by ACh was abolished by L-NAME plus ODQ, but not affected by the apamin plus TRAM-34 combination, indicating that NOS-derived nitrogen oxide species are the predominant endothelium-derived vasodilators in sham and diabetic rat carotid arteries. The maximum relaxation to ACh was significantly decreased by L-cysteine in both sham and diabetic rats, whereas HXC attenuated ACh-induced relaxation only in sham rats, suggesting that diabetes impaired the contribution of NO•, whereas HNO-mediated vasorelaxation remained intact.Conclusion: Both NO• and HNO contribute to endothelium-dependent relaxation in carotid arteries. In diabetes, NO•-mediated relaxation is impaired, whereas HNO-mediated relaxation was preserved. The potential for preserved HNO activity under pathological conditions that are associated with oxidative stress indicates that HNO donors may represent a viable therapeutic approach to the treatment of vascular dysfunction.

Methylene blue alleviates endothelial dysfunction and reduces oxidative stress in aortas from diabetic rats

2018 ◽  
Vol 96 (10) ◽  
pp. 1012-1016 ◽  
Author(s):  
Andreea I. Privistirescu ◽  
Alexandra Sima ◽  
Oana M. Duicu ◽  
Romulus Timar ◽  
Mariana G. Roșca ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Methylene Blue ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Ex Vivo ◽  
Xylenol Orange ◽  
Diabetic Rat ◽  
Ros Production ◽  
Protective Effects

Endothelial dysfunction and the related increase in reactive oxygen species (ROS) production are important events in the pathophysiology of diabetes mellitus (DM). Methylene blue (MB) has been systematically investigated for its protective effects against refractory hypotension and mitochondrial dysfunction. We have previously demonstrated that MB improved mitochondrial respiration and partially decreased oxidative stress in diabetic rat hearts. The present study was aimed to investigate whether MB modulates vascular function and ROS production in thoracic aortic rings isolated from rats with streptozotocin-induced DM (after 4 weeks of hyperglycemia). The effects of MB (0.1 μM, 30 min ex vivo incubation) on vascular reactivity in organ chamber (phenylephrine-induced contraction, acetylcholine-induced relaxation) and H2O2production (assessed by ferrous iron xylenol orange oxidation assay) were investigated in vascular preparations with intact endothelium and after denudation. DM elicited a significant alteration of vascular function: increased contractility to phenylephrine, attenuation of acetylcholine-dependent relaxation, and augmented H2O2generation. Ex vivo incubation with MB partially reversed all these changes (by approximately 70%) in vascular segments with intact endothelial layer (but not in denuded vessels). In conclusion, MB might be useful in alleviating endothelial dysfunction and mitigating endothelial oxidative stress, observations that clearly require further investigation in the setting of cardiometabolic disease.

Chronic intermittent hypobaric hypoxia provides vascular protection in the aorta of the 2-kidney, 1-clip rat model of hypertension

2018 ◽  
Vol 96 (8) ◽  
pp. 807-814
Author(s):  
Congrui Fu ◽  
Na Li ◽  
Yujia Yuan ◽  
Ri Wang ◽  
Jinting Chen ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Rat Model ◽  
Hypobaric Hypoxia ◽  
Critical Factor ◽  
Rat Aorta ◽  
Reduce Blood Pressure ◽  
Vascular Protection ◽  
Spontaneously Hypertensive ◽  
Intermittent Hypobaric Hypoxia ◽  
Endothelium Dependent Relaxation

Many studies have demonstrated that chronic intermittent hypobaric hypoxia (CIHH) can reduce blood pressure in spontaneously hypertensive rats and renovascular hypertensive (RVH) rats in which endothelial dysfunction is determined as a critical factor. However, whether CIHH can regulate vasodilation of the aorta in RVH rats remains unknown. The purpose of this study was to investigate the effect of CIHH on impaired relaxation of the aorta in the 2-kidney, 1-clip (2K1C) RVH rat model. The results showed CIHH improved the impaired endothelium-dependent relaxation in the 2K1C rat aorta. The endothelial dysfunction was prevented by the p38 antagonist SB203580, but not by the ERK1/2 antagonist PD98059 or JNK antagonist SP600125. Furthermore, the expression of p-eNOS, HIF-1α, and HIF-2α increased while that of p-p38 and BMP-4 decreased in CIHH-treated aortas from 2K1C rats. Finally, the p-eNOS expression was upregulated and the p-p38 expression was downregulated by pre-incubation of SB203580 or the BMP-4 antagonist Noggin with the aorta. CIHH ameliorated the impairment of endothelium-dependent relaxation through upregulating the expression of p-eNOS, which may be mediated by the inhibition of BMP-4/p-p38 MAPK, and upregulating the expression of HIFs in the 2K1C rat aorta.

Effects of empagliflozin on oxidative stress and endothelial dysfunction in STZ-induced Type 1 diabetic rat

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
M Oelze ◽  
S Kröller-Schön ◽  
M Mader ◽  
E Zinßius ◽  
P Stamm ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Diabetic Rat

Exploration of the Effect and Mechanism of ShenQi Compound in a Spontaneous Diabetic Rat Model

2019 ◽  
Vol 19 (5) ◽  
pp. 622-631 ◽  
Author(s):  
Ya Liu ◽  
Jian Kang ◽  
Hong Gao ◽  
Xiyu Zhang ◽  
Jun Chao ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Signaling Pathway ◽  
Rat Model ◽  
Mtor Signaling ◽  
Diabetic Rat ◽  
Gene Microarray ◽  
Mtor Signaling Pathway ◽  
Glucose Fluctuation ◽  
Blood Glucose Fluctuation ◽  
Diabetic Rat Model

Background: Type 2 Diabetes Mellitus (T2DM) is a world-wide metabolic disease with no cure from drugs and treatment. In China, The Traditional Chinese Medicine (TCM) herbal formulations have been used to treat T2DM for centuries. Methods: In this study, we proposed a formula called ShenQi Compound (SQC), which has been used in clinical therapeutics in China for several years. We evaluated the effect of SQC in a spontaneous diabetic rat model (GK rats) by detecting a series of blood indicators and performing histological observations. Meanwhile, the gene microarray and RT-qPCR experiments were used to explore the molecular mechanism of SQC treatment. In addition, western medicine, sitagliptin was employed as a comparison. Results: The results indicated that SQC and sitagliptin could effectively improve the serum lipid (blood Total Cholesterol (TC) and blood Triglycerides (TG)), hormone levels (serum insulin (INS), Glucagon (GC) and Glucagon-Like Peptide-1 (GLP-1)), alleviated the inflammatory response (hypersensitive C-Reactive Protein (hsCRP)), blood glucose fluctuation (Mean Blood Glucose (MBG), standard deviation of blood glucose (SDBG) and Largest Amplitude of plasma Glucose Excursions (LAGE)), pancreatic tissue damage and vascular injury for T2DM. Compared with sitagliptin, SQC achieved a better effect on blood glucose fluctuation (p<0.01). Meanwhile, the gene microarray and RT-qPCR experiments indicated that SQC and sitagliptin may improve the T2DM through affecting the biological functions related to apoptosis and circadian rhythm. Moreover, SQC might be able to influence the mTOR signaling pathway by regulating Pik3r1, Ddit4 expression. Conclusion: All these results indicate that SQC is an effective therapeutic drug on T2DM. Notably, SQC presents an obvious blood glucose fluctuation-preventing ability, which might be derived from the regulation of the mTOR signaling pathway.

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