Studies of acteoside and its derivatives on selected aspects of cardiovascular disease: hemorheology, endothelial inflammation and hypertension

Autor: Chao-Hsiang Chen, 陳兆祥
Rok vydání: 2011
Druh dokumentu: 學位論文 ; thesis
Popis: 99
Cardiovascular disease, a common name for a variety of diseases that affect heart and blood vessels, is a major killer of women and men in the United States. Hemorheologic abnormality parameters, vascular endothelial cell inflammation and hypertension are the three main causes on the induction of cardiovascular disease. In the first part of this thesis, we established an in vitro model to evaluate the influence of hyperbaric oxygen (HBO) on hemorheological parameters. A well-sealed chamber with HBO was used to simulate an environment of free radical attacks. Hemorheological parameters, including whole blood viscosity, erythrocyte membrane lipid peroxidation, and erythrocyte deformability, were investigated. Results show that an increase in oxygen partial pressure (1.0, 1.5, 2.0 and 2.5 atm) and exposure time (4, 8, 12 and 16 h) led to elevated levels of superoxide and viscosity of whole blood, enhanced lipid peroxidation in erythrocyte membranes, as well as decreased erythrocyte deformability. We then used some well-known catechin antioxidants, such as epigallocatechin gallate (EGCG), (-)-epicatechin 3-gallate (ECG), and (-)-epigallocatechin (EGC) to verify the feasibility on abnormal hemorheological parameters induced by hyperbaric oxygen. We found that EGCG, ECG, and EGC (0.1, 0.5 and 1.0 μM) effectively ameliorated hemorheologic abnormality and enhanced erythrocyte deformability. Moreover, we used the established model for evaluating the ameliorative effect of phenylethanoid glycosides, such as acteoside and 6-O-acetylacteoside, on hemorheological abnormality. We found that acteoside exhibited stronger ameliorative effect on hemorheologic abnormality induced by HBO treatment than that of 6-O-acetylacteoside. Cell adhesion molecules (CAMs) play an important role on atherosclerosis and vascular endothelial cell inflammation. Acteoside has been shown to possess anti-inflammatory properties in vitro. However, it is unclear whether acteoside and similar compounds may inhibit the expression of CAMs. In the second part of this thesis, we examined the inhibitory effects of acteoside, isoacteoside and 6-O-acetylacteoside on leukocyte adhesion to human umbilical vein endothelial cells (HUVECs) and the expression of ICAM-1 andVCAM-1 induced by a pro-inflammatory cytokine, IL-1β. We found that acteoside, isoacteoside and 6-Oacetylacteoside possessed an inhibitory effect on IL-1β-activated expression of intercellular CAM-1 (ICAM-1) and vascular CAM-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). The inhibitory potency was 6-O-acetylacteoside > acteoside > isoacteoside. Moreover, Acteoside and 6-O-acetylacteoside also dose-dependently inhibit VCAM-1 gene promoter activity in IL-1β-activated HUVECs. In addition, we investigated the effect of acteoside and 6-O-acetylacteoside on phosphorylation of activation of ERK, JNK, and p38, all of which participate in the expression of ICAM-1 and VCAM-1. The inhibition of acteoside and 6-O-acetylacteoside on IL-1β-activated expression of CAMs was manifested by decreased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). These results indicated that acteoside and 6-O-acetylacteoside exert potential anti-inflammatory activities in vascular endothelium by inhibiting the expression of CAMs, primarily through decreased phosphorylation of ERK and JNK. Acteoside has been shown to induce a dose-dependent decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP) following its intravenous injection into normotensive anaesthetized Wistar rats. However, it is unclear whether oral supplementation of Acteoside is useful for blood pressure regulation in vivo and few studies have compared side-by-side the in vivo antihypertensive activities of Acteoside and its structurally related compounds such as Isoacteoside. Therefore, in the third part of this thesis, we investigated the antihypertensive activities of Acteoside and its structural isomer, isoacteoside, in spontaneously hypertensive rats (SHR) and their in vitro effects on angiotensin-converting enzyme (ACE) activity and in vitro antioxidant activities. Results revealed that orally administrated a signal dose (10 mg/kg BW) of Acteoside, but not Isoacteoside, significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP) over a 24–h period. Both Acteoside and Isoacteoside significantly inhibited the activities of ACE, but the effects of Acteoside were stronger than those of Isoacteoside. Both compounds scavenged DPPH radical and inhibited xanthine oxidase to a similar extent, whereas Isoacteoside was more effective than Acteoside in scavenging superoxide radicals (IC50 = 38.5 μM and 66.0 μM, respectively). These results demonstrate that Acteoside but not Isoacteoside exhibits antihypertensive effects in SHR, and that the effect of Acteoside is primarily related to its inhibition of ACE but not its antioxidant activities. Further studies on the potential antihypertensive effects of Acteoside are warranted. In summary, this dissertation has established an in vitro model for screening or assessing the efficacy of functional foods and drugs in the prevention or improvement of hemorheologic abnormality. The inhibitory role of acteoside on HBO-induced hemorheologic abnormality parameters has significant improvements, such as the reduction on erythrocyte membrane lipid peroxidation, and the increase of erythrocyte deformability. In addition, acteoside was also found to inhibit endothelial cell inflammation through inhibition the expression of CAMs induced by IL-1β. Moreover, acteoside exhibits antihypertensive effects in SHR. Therefore, acteoside possess potential to be developed as functional food and drug on the prevention of cardiovascular disease.
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