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Ginkgolide B Increases Hydrogen Sulfide and Protects Against Endothelial Dysfunction in Diabetic Rats

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Ginkgolide B Increases Hydrogen Sulfide and Protects Against Endothelial Dysfunction in Diabetic Rats 4 DISEASE-RELATED CHANGES IN BLOOD VESSELS Croat Med J. 2015;56:4-13 doi: 10.3325/cmj.2015.56.4 Ginkgolide B increases Guo-Guang Wang1*, Qing- Ying Chen2*, Wei Li1, Xiao- hydrogen sulfide and protects Hua Lu1, Xue Zhao1 1Department of Pathophysiology, against endothelial dysfunction Wannan Medical College, Wuhu, in diabetic rats People’s Republic of China 2General Hospital of Jinan Military Command, Jinan, People’s Republic of China *Contributed equally to the study. Aim To evaluate the effect of ginkgolide B treatment on vascular endothelial function in diabetic rats. Methods The study included four groups with 15 male Sprague-Dawley rats: control group; control group treat- ed with ginkgolide B; diabetic group; and diabetic treat- ed with ginkgolide B. The activity of superoxide dismutase (SOD), malondialdehyde content, and nicotinamide ade- nine dinucleotide phosphate (NADPH) oxidase subunits, and glutathione peroxidase 1 (GPX1) protein expression were determined in aortic tissues. Vasoconstriction to phe- nylephrine (PHE) and vasorelaxation to acetylcholine (Ach) and sodium nitroprusside (SNP) were assessed in aortic rings. Nitric oxide (NO) and hydrogen sulfide (H2S) were measured, as well as cystathionine γ lyase (CSE) and cys- tathionine β synthetase (CBS) protein expression, and en- dothelial nitric oxide synthase (eNOS) activity. Results Diabetes significantly impaired PHE-induced va- soconstriction and Ach-induced vasorelaxation (P < 0.001), reduced NO bioavailability and H2S production (P < 0.001), SOD activity, and GPX1 protein expression (P < 0.001), and increased malondialdehyde content and NADPH oxidase subunits, and CSE and CBS protein expression (P < 0.001). Ginkgolide B treatment improved PHE vasoconstriction and Ach vasorelaxation (P < 0.001), restored SOD (P = 0.005) and eNOS (P < 0.001) activities, H2S production (P = 0.044) and decreased malondialdehyde content (P = 0.014). Vas- orelaxation to SNP was not significantly different in control and diabetic rats with or without ginkgolide B treatment. Besides, ginkgolide B increased GPX1 protein expression and reduced NADPH oxidase subunits, CBS and CSE pro- Received: August 13, 2014 tein expression. Accepted: February 17, 2014 Conclusion Ginkgolide B alleviates endothelial dysfunc- Correspondence to: tion by reducing oxidative stress and elevating NO bio- Guo-guang Wang availability and H2S production in diabetic rats. Department of Pathophysiology School of Basic Medicine, Wannan Medical College 22 # West of Wenchang Road Wuhu, China [email protected] www.cmj.hr Wang et al: Effect of ginkgolide B treatment on vascular endothelial function 5 Diabetes mellitus is an endocrine disease caused by de- leaves. Many studies have demonstrated that ginkgolide B creased insulin secretion or action, leading to impaired can inhibit platelet-activating factor (PAF)-induced platelet glucose and lipid metabolism (1). The most dangerous activation via binding with PAF receptor (20,21). Therefore, complication of diabetes mellitus is cardiovascular dis- ginkgolide B is widely used as a natural antagonist of PAF ease, which is the primary factor leading to high mortality and inhibitor of PAF-induced inflammatory reaction (22). It and morbidity in diabetic patients (2). A critical role in dia- has been shown that ginkgolide B regulates many physi- betic cardiovascular complications is played by endothe- ologic functions, including the antioxidant function, im- lial dysfunction. Mechanisms responsible for endothelial proving the cognitive functions of central nervous system dysfunction are still poorly understood, but hyperglyce- (23,24), repressing atherosclerosis (25), and abating liver mia-induced oxidative stress is hypothesized to be one of cirrhosis (26). In this study, we investigated the effects of them (3). Increased blood glucose increases reactive oxy- ginkgolide B on endothelial function and mediators such gen species (ROS) production via glucose auto-oxidation as hydrogen sulfide (H2S), biomarkers of oxidative stress, (4) and variation in activity of oxidoreductases, such as NA- and oxidoreductase in the aorta of rats with streptozoto- DPH oxidase (5). ROS can impair vascular function by dam- cin-induced diabetes. aging endothelial cells, thus playing an important role in diabetes and its cardiovascular complications (6). NADPH METHODS oxidase is important because it generates ROS (7,8). Gluta- thione peroxidase 1 (GPX1) is one of the pivotal antioxidant Experimental animals enzymes in vascular endothelium, which protects against the presence of coronary artery disease (9). Its overexpres- Sixty 8-10 weeks old male Sprague-Dawley rats (180-220 sion reduces ROS formation and enhances phosphoryla- g) were purchased from the central animal laboratory of tion of endothelial nitric oxide synthase (eNOS), which im- Wannan Medical College. All experimental procedures proves endothelial function (10). were approved by the Academic Experimental Animal Care and Use Committee of Wannan Medical College. Ani- Hydrogen sulfide (H2S) was previously considered only mals received a standard pellet diet and water ad libitum, as a toxic gas, but recent studies have suggested that and were raised for 2 weeks in a standard animal laboratory it plays a variety of important physiological and phys- at 22 ± 2°C temperature and with a 12-hour daylight cycle iopathological roles (11,12). H2S is generated from L- for acclimatization before the experiment. cysteine by several enzymes including cystathionine γ lyase (CSE) and cystathionine β synthetase (CBS). Some After 12 hours of fasting, thirty rats were intraperitoneal- studies have shown that H2S takes part in modulation of ly injected STZ (65 mg/kg) dissolved in 0.1 mol/L natrium cardiovascular system (13,14). It has also been shown that citricum buffer (pH 4.5) for induction of diabetes mellitus. H2S biosynthesis is impaired in diabetes, and that it may Thirty control rats were injected with the same volume be effective to administer different2 H S donors to diabetic buffer. All rats received a standard chow and water. After 72 animals (15,16). hours of STZ treatment, blood was drawn from the tail vein to measure the levels of the fasting blood glucose for con- The risk of endothelial dysfunction is increased by sus- firmation of diabetes mellitus. Rats with the fasting glucose tained progression of hyperglycemia and hyperlipidemia. values >15 mmol/L were regarded as diabetic and used for Endothelial dysfunction is characterized by alterations of further experiments. endothelium-dependent vascular response to vasocon- strictors and vasodilators in diabetic animals (17,18). There- Experimental protocol and treatment fore, cardiovascular complications including endothelial dysfunction in patients with diabetes have been treated After diabetes was confirmed, control and diabetic rats by decreasing blood glucose and lipid content, and reduc- were randomly divided into four groups as follows: a) con- ing activation of angiotensin. However, these treatments trol group (CG, n = 15): rats received standard food and wa- have not prevented the development of complications ter; b) control treated group (CT, n = 15): rats were treated (19), emphasizing the need for novel approaches. with 5 mg/kg/d ginkgolide B and received standard food and water; c) diabetic group (DG, n = 15): rats received Ginkgolide B, a plant-derived terpenoid, is one of natural standard food and water; d) diabetic treated group (DT, bioactive components from the extract of ginkgo biloba n = 15): rats were treated with 5 mg/kg/d ginkgolide www.cmj.hr 6 DISEASE-RELATED CHANGES IN BLOOD VESSELS Croat Med J. 2015;56:4-13 B and received standard food and water. Ginkgolide B was used as a model of vasomotoricity (28). Briefly, after animals given orally by gavage for 8 weeks. were sacrificed, the thoracic aortas were immediately har- vested, and blood and surrounding connective tissue was Biochemical analyses of blood samples cleared away in the plate filled with Krebs-Henseleit buffer (KH buffer, pH 7.4) with sodium chloride (118 mmol/L), po- At the end of the experiment, body weight was measured, tassium chloride (4.7 mmol/L), monopotassium phosphate and blood specimens were collected into prechilled test (1.2 mmol/L), magnesium sulfate (1.2 mmol/L), sodium bi- tubes. To assess the change of blood glucose and serum carbonate (25 mmol/L), glucose (5.5 mM), and calcium lipid profiles, blood specimens were centrifugated at chloride (2.5 mmol/L). The aortas were carefully cut into 1300 × g for separation of serum. Concentrations of serum 3-4 mm aortic rings. The endothelial layer was removed in lipid profiles were determined by the enzymatic colori- certain experiments so that the effects of the endothelium metric methods (commercial kits from Nanjing Jiancheng on vascular responses can be observed. The arterial rings Bioengineering Institute, Nanjing, China). were fixed in the tissue chamber with KH buffer with ac- cess to 95% O2 and 5% CO2 gas mixtures at 37°C, and were Measurement of oxidative stress, eNOS activity, and connected to tension sensor and stainless wire in the bot- nitric oxide (NO) production tom of the chamber. After eight weeks of ginkgolide B treatment, rats were After 60 minutes equilibration, concentration-dependent anesthetized with sodium pentobarbital and euthanized, vasoconstriction to phenylephrine (PHE, α-adrenoceptor and blood samples and aortic tissues were immediately agonist) was observed. To estimate the effect of ginkgolide collected. For
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