Hye Yoom Kim

Hypotensive, Hypolipidemic, and Vascular Protective Effects of Morus alba L. in Rats Fed an Atherogenic Diet

Morus alba L. has been used in traditional Chinese medicine and almost all parts of this plant are useful in cardiovascular, liver and spleen disorders. The present study was designed to investigate the inhibitory effect of a water extract from Morus alba L. (WMA) on vascular dysfunction in rat models fed a high fat and high cholesterol diet. Male rats were fed an atherogenic diet consisting of food with 7.5% cocoa butter and 1.25% cholesterol, with or without 100 or 200 mg/day/kg WMA, for 14 weeks. Chronic treatment with low (100 mg/kg/day) or high (200 mg/day/kg) doses of WMA markedly attenuated hypertension and the impairments of acetylcholine-induced relaxation of aortic rings in rats fed an atherogenic diet. WMA reduced intima/media thickness in rats fed an atherogenic diet. WMA improved plasma levels of triglyceride (TG) and augmented plasma levels of high-density lipoprotein (HDL) and plasma low-density lipoprotein (LDL), but did not affect blood glucose levels. Interestingly, WMA suppressed increased cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) expression in the aorta. Taken together, these results suggested that Morus alba L. could improve an atherogenic diet-induced hypertension, hyperlipidemia, and vascular dysfunction through inhibition of cell adhesion molecules expression and induction of vascular relaxation.

Water extract of Zanthoxylum piperitum induces vascular relaxation via endothelium-dependent NO-cGMP signaling

AIM OF THE STUDY The aim of the present study was to define the effects of extracts of leaves of Zanthoxylum piperitum (ZP) on the vascular tension and its mechanisms responsible in rat thoracic aortic rings. MATERIALS AND METHODS Methanol extract of ZP and aqueous fraction of the methanol extract (AZP) were examined for their vascular relaxant effects in isolated phenylephrine-precontracted aortic rings. RESULTS Methanol extract of ZP and aqueous fraction of the methanol extract (AZP) induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Endothelium-denudation abolished the AZP-induced vasorelaxation. Pretreatment of the endothelium-intact aortic rings with N(G)-nitro-L-arginine methylester (L-NAME) and 1H-[1,2,4]-oxadiazolo-[4,3-alpha]-quinoxalin-1-one (ODQ) inhibited the AZP-induced vasorelaxation. Inhibition of Ca(2+) entry via L-type Ca(2+) channels failed to block the AZP-induced vasorelaxation. Extracellular Ca(2+) depletion slightly but significantly attenuated the AZP-induced vasorelaxation. Thapsigargin significantly attenuated the AZP-induced vasorelaxation. Further, Gd(3+) and 2-aminoethyl diphenylborinate (2-APB), inhibitors of store-operated Ca(2+) entry (SOCE), markedly attenuated the AZP-induced vasorelaxation. Also, wortmannin, an inhibitor of Akt, an upstream signaling molecule of eNOS, attenuated the AZP-induced vasorelaxation. AZP increased cGMP levels of the aortic rings in a concentration-dependent manner and the effect was blocked by L-NAME, ODQ, thapsigargin, Gd(3+), 2-APB, and wortmannin. K(+) channel inhibition with glibenclamide and tetraethylammonium, cyclooxygenase inhibition with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on the AZP-induced vasorelaxation. CONCLUSION Taken together, the present study suggests that AZP relaxes vascular smooth muscle via endothelium-dependent activation of NO-cGMP signaling through the Akt- and SOCE-eNOS pathways.

Vascular relaxation by ethanol extract of Xanthoceras sorbifolia via Akt- and SOCE-eNOS-cGMP pathways.

AIM OF THE STUDY The aim of the present study was to define the effect of Xanthoceras sorbifolia extracts (XS) on vascular tension and responsible mechanisms in rat thoracic aortic rings. MATERIALS AND METHODS Ethanol extract of the leaves of XS (EXS) was examined for their vascular relaxant effects in isolated phenylephrine-precontracted rat thoracic aorta. RESULTS EXS (0.1-100 μg/ml) induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Endothelium-denudation abolished EXS-induced vasorelaxation. Pretreatment of the endothelium-intact aortic rings with N(G)-nitro-L-arginine methylester (L-NAME) and 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ) inhibited EXS-induced vasorelaxation. Inhibition of Ca(2+) entry via L-type Ca(2+) channels failed to block the EXS-induced vasorelaxation. Extracellular Ca(2+) depletion significantly attenuated EXS-induced vasorelaxation. Modulators of the store-operated Ca(2+) entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate (2-APB) and Gd(3+), and an inhibitor of Akt, wortmannin, markedly attenuated the EXS-induced vasorelaxation. EXS increased cGMP levels of the aortic rings in a concentration-dependent manner and the effect was blocked by L-NAME, ODQ, thapsigargin, Gd(3+), 2-APB, and wortmannin. Further, EXS-induced vasorelaxation was significantly attenuated by tetraethylammonium, a non-selective K(ca) channels blocker, but not by glibenclamide, an ATP-sensitive K(+) channels inhibitor. Inhibition of cyclooxygenase with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on EXS-induced vasorelaxation. CONCLUSIONS The present study suggests that EXS relaxes vascular smooth muscle via endothelium-dependent NO-cGMP signaling through activation of the Akt- and SOCE-eNOS-sGC pathways, which may, at least in part, be related to the function of K(+) channels.

Fermented Red Ginseng Potentiates Improvement of Metabolic Dysfunction in Metabolic Syndrome Rat Models

Metabolic syndrome including obesity, dyslipidemia and hypertension is a cluster of risk factors of cardiovascular disease. Fermentation of medicinal herbs improves their pharmacological efficacy. Red ginseng (RG), a widely used traditional herbal medicine, was reported with anti-inflammatory and anti-oxidant activity. Aim in the present study was to investigate that the effects of fermented red ginseng (FRG) on a high-fructose (HF) diet induced metabolic disorders, and those effects were compared to RG and losartan. Animals were divided into four groups: a control group fed a regular diet and tap water, and fructose groups that were fed a 60% high-fructose (HF) diet with/without RG 250 mg/kg/day or FRG 250 mg/kg/day for eight weeks, respectively. Treatment with FRG significantly suppressed the increments of body weight, liver weight, epididymal fat weight and adipocyte size. Moreover, FRG significantly prevented the development of metabolic disturbances such as hyperlipidemia and hypertension. Staining with Oil-red-o demonstrated a marked increase of hepatic accumulation of triglycerides, and this increase was prevented by FRG. FRG ameliorated endothelial dysfunction by downregulation of endothelin-1 (ET-1) and adhesion molecules in the aorta. In addition, FRG induced markedly upregulation of Insulin receptor substrate 1 (IRS-1) and glucose transporter type 4 (Glut4) in the muscle. These results indicate that FRG ameliorates obesity, dyslipidemia, hypertension and fatty liver in HF diet rats. More favorable pharmacological effects on HF diet induced metabolic disorders were observed with FRG, compared to an equal dose of RG. These results showed that the pharmacological activity of RG was enhanced by fermentation. Taken together, fermentated red ginseng might be a beneficial therapeutic approach for metabolic syndrome.

Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats

Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC) is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks) significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP), total bilirubin, leptin, and insulin in rats with induced metabolic syndrome. BC markedly prevented increased adipocyte size and hepatic triglyceride accumulation in rats with induced metabolic syndrome. BC suppressed oral glucose tolerance and protein expression of insulin receptor substrate-1 (IRS-1) and phosphorylated AMP-activated protein kinase (p-AMPK) in muscle. BC significantly suppressed plasma total cholesterol, triglyceride, and LDL content. BC suppressed endothelial dysfunction by inducing downregulation of endothelin-1 and adhesion molecules in the aorta. Vascular relaxation of thoracic aortic rings by sodium nitroprusside and acetylcholine was improved by BC. The present study provides evidence of the potential protective effect of BC against metabolic syndrome by demonstrating improvements in dyslipidemia, hypertension, insulin resistance, and obesity in vivo.

Effect of Atractylodes macrocephala on Hypertonic Stress-Induced Water Channel Protein Expression in Renal Collecting Duct Cells

Edema is a symptom that results from the abnormal accumulation of fluid in the body. The cause of edema is related to the level of aquaporin (AQP)2 protein expression, which regulates the reabsorption of water in the kidney. Edema is caused by overexpression of the AQP2 protein when the concentration of Na+ in the blood increases. The rhizome of Atractylodes macrocephala has been used in traditional oriental medicine as a diuretic drug; however, the mechanism responsible for the diuretic effect of the aqueous extract from A. macrocephala rhizomes (AAMs) has not yet been identified. We examined the effect of the AAM on the regulation of water channels in the mouse inner medullary collecting duct (mIMCD)-3 cells under hypertonic stress. Pretreatment of AAM attenuates a hypertonicity-induced increase in AQP2 expression as well as the trafficking of AQP2 to the apical plasma membrane. Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor known to play a central role in cellular homeostasis by regulating the expression of some proteins, including AQP2. Western immunoblot analysis demonstrated that the protein and mRNA expression levels of TonEBP also decrease after AAM treatment. These results suggest that the AAM has a diuretic effect by suppressing water reabsorption via the downregulation of the TonEBP-AQP2 signaling pathway.

Beneficial Effects of Scutellaria baicalensis on Penile Erection in Streptozotocin-Induced Diabetic Rats

We have reported that ethanol extracts of the root from Scutellaria baicalensis Georgi (ESB) relax cavernous smooth muscles via the NO/cGMP system and Ca[Formula: see text]-sensitive K[Formula: see text] channels in the rabbit corpus cavernosum. In the present study, erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrical stimulation of the cavernous nerve. The ICP/MAP ratio was dose-dependently increased by the treatment of ESB in normal SD rats ([Formula: see text]). To investigate the beneficial effect of ESB on erectile dysfunction in a diabetic animal model, male SD rats were injected with streptozotocin (60[Formula: see text]mg/kg) and then 300[Formula: see text]mg/kg/day ESB was administered daily for eight weeks. In our in vivo study, administration of ESB in STZ rats significantly increased the ICP, ICP/MAP ratio, area under the curve (AUC), as well as the cavernous cGMP levels. Morphometric analyses showed that ESB administration increased both smooth muscle volume and the regular arrangement of collagen fibers compared to the STZ group. The protein expression levels of endothelial nitric oxide synthase (eNOS) and SM [Formula: see text]-actin from penile tissues were also significantly increased in the ESB-treated rats. Taken together, these results suggest that ESB ameliorates penile erectile dysfunction via the activation of the NO/cGMP pathways of the penile corpus cavernosum in a streptozotocin-induced diabetic rat model.

Oleanolic acid increases plasma ANP levels via an accentuation of cardiac ANP synthesis and secretion in rats

Oleanolic acid is known to have beneficial effects on the regulation of cardiovascular homeostasis. The present study was designed to identify the effects of oleanolic acid on plasma levels and atrial synthesis and secretion of atrial natriuretic peptide (ANP). Experiments were performed in rats and isolated perfused beating rat atria. ANP was measured using a selective radioimmunoassay. ANP mRNA expression was measured using real-time quantitative polymerase chain reaction. Administration of oleanolic acid increased plasma ANP levels in a dose-related manner. Similarly, oleanolic acid increased atrial ANP content and ANP mRNA expression. To evaluate the effects of oleanolic acid on ANP secretion, atrial stretch and muscarinic acetylcholine receptor activation were applied to the atria from rats chronically treated with oleanolic acid. Baseline levels of ANP secretion were higher in the atria from rats treated with oleanolic acid compared to rats treated with vehicle. Furthermore, oleanolic acid treatment enhanced the stretch-induced increase in ANP secretion. Acetylcholine in the presence of isoproterenol increased ANP secretion. The acetylcholine-induced increase in ANP secretion was also enhanced in the atria from rats treated with oleanolic acid compared to atria from rats treated with vehicle. The present findings indicate that oleanolic acid increases plasma ANP levels via increased ANP synthesis and secretion in rats. It is proposed that an accentuation of the ANP system is involved in the beneficial effects of oleanolic acid on the regulation of cardiovascular homeostasis.

Bakuchicin induces Vascular Relaxation via Endothelium‐dependent NO‐cGMP Signaling

Bakuchicin is a furanocoumarin derived from the seeds of Psoralea corylifolia. The aim of the present study was to investigate the effect of bakuchicin on vascular tone in rat aortic tissue. Bakuchicin induced a dose‐dependent relaxation of phenylephrine‐precontracted rat aorta which was abolished by removal of the endothelium. Pretreatment of the endothelium‐intact aortic tissues with NG‐nitro‐ l‐arginine methylester (L‐NAME) or 1H‐[1,2,4]‐oxadiazole‐[4,3‐α]‐quinoxalin‐1‐one (ODQ) significantly inhibited the vascular relaxation induced by bakuchicin. Incubation with bakuchicin increased the production of cGMP in a concentration‐dependent manner, and this effect was blocked by pretreatment with both L‐NAME and ODQ. Vascular relaxation induced by bakuchicin was significantly inhibited by pretreatment with verapamil and diltiazem, but not by several other inhibitors including tetraethylammonium (TEA), glibenclamide, indomethacin, atropine or propranolol. These results suggested that bakuchicin‐induced vasodilatation is closely associated with the endothelium‐dependent nitric oxide (NO)/cGMP signaling pathway, with the possible involvement of L‐type Ca2+channels. Copyright

Protective effect of betulinic acid on early atherosclerosis in diabetic apolipoprotein-E gene knockout mice

ABSTRACT Atherosclerosis, a chronic and progressive disease, is a leading cause of endothelial dysfunction, diabetes mellitus, hypertension, and hypercholesterolemia. Betulinic acid (BA), a pentacyclic triterpene, has been reported to have a variety of biological effects, including anti‐inflammatory and immunomodulatory properties. This study was designed to determine whether BA could prevent atherosclerosis in diabetic apolipoprotein‐E gene knockout (ApoE KO) mice. The mice were treated with BA for 12 weeks to examine its beneficial effects on atherosclerosis in ApoE KO mice. Male ApoE KO mice and age‐matched control group mice (C57BL/6Jms) were used as experimental systems and their systolic blood pressure, insulin resistance, and vascular inflammation were measured. BA‐treated ApoE KO mice showed lowered systolic blood pressure. The metabolic parameter showed that BA decreased blood urea nitrogen, triglyceride, and total cholesterol levels. Blood glucose, insulin, glucose tolerance results, and the homeostasis model assessment of insulin resistance (HOMA‐IR) index were found to be better in BA‐treated ApoE KO mice than untreated ApoE KO mice. Consistent with the change in lipid profiles, oil red O and H&E staining revealed that treatment with BA reduced atherosclerotic lesions such as roughened endothelial layers. BA ameliorated the reduction of endothelial nitric oxide synthase (eNOS) expression, leading to the inhibition of intracellular adhesion molecule 1 (ICAM‐1) and endothelin 1 (ET‐1) expression. These results suggest that BA may be useful in the treatment and prevention of early atherosclerosis via the attenuation of endothelial dysfunction in diabetic ApoE KO mice. Graphical abstract Figure. No caption available.