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標題: | Pyridoxamine 降低膠原蛋白醣化作用,可預防老年 Fisher 344 老鼠主動脈硬化與降低血管阻力 Pyridoxamine prevents age-related aortic stiffening and vascular resistance in association with reduced collagen glycation in aged Fisher 344 rats. |
作者: | En-Ting Wu 吳恩婷 |
指導教授: | 張國柱 |
關鍵字: | 老化,心血管,阻抗,高度醣化終產物,pyridoxamine, aging,cardiovascular,impedance,advanced glycation end product,pyridoxamine, |
出版年 : | 2014 |
學位: | 博士 |
摘要: | 老化引起許多心血管變化,包括高血壓、血管硬化、心肌肥厚等。其中的作用機轉很多,本論文主要是針對高度醣化終產物 (advanced glycation end products, AGE) 和老化血管的關係,因高度醣化終產物與高度脂氧化終產物 (advanced lipoxidation end products, ALE) 而導致組織內蛋白質氧化性化學修飾增加,已知與正常老化有關。有許多物質可能可以阻擋 AGE/ALE 的後續反應,Pyridoxamine (PM) 是其中一種。 PM 為三種自然形式的維生素 B6 之一,已確認能夠抑制碳水化合物的自氧化作用和脂質的過氧化作用所產生的 AGE/ALE。 本試驗旨在探討 PM 介入是否能抑制醣化膠原蛋白的病理性交聯作用 (cross-linking),而預防老年主動脈硬化及血管阻抗的上升。
本實驗中,我們使用 15 月齡的雄性 Fisher 344 大鼠,每日給予 PM (1 g l-1,加入飲水中) 共五個月,於 20 月齡時與同齡、未用藥的控制組比較,同時也和六個月大的大鼠來做比較以證實老化在大鼠的心血管影響。我們測定脈衝式主動脈壓與血流訊號,接著用於血管阻抗分析。此外,採用蛋白質點漬分析法,以 AGE 抗體 6D12 偵測主動脈膠原蛋白上因醣化作用所產生的修飾作用。我們發現 PM 治療減緩了周邊血管總阻力因年齡而增加的情形。PM 促使波傳輸時間及主動脈容積增加,顯示 PM 能夠增進老化血管組織的主動脈擴張度,同時也減低主動脈上 AGE 與膠原蛋白的交聯作用。波傳輸時間增加,波反射係數減低,也顯示老年動物的 PM 治療能夠預防心臟血流負荷因老化而加重。這些發現顯示,老年大鼠使用 PM 後,能夠減少主動脈上 AGE 與膠原蛋白的病理性的交聯作用,有助於改善動脈力學。 An increase in oxidative chemical modifications of tissue proteins by advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs) has been implicated in normal aging. Pyridoxamine (PM), one of the three natural forms of vitamin B6, has been identified as an inhibitor of AGE/ALE products formed during the autoxidation of carbohydrates and peroxidation of lipids. The current study seeks to determine whether PM intervention could prevent the age-related aortic stiffening and vascular resistance through its ability to inhibit the pathogenic cross-linking of glycated collagen. Male Fisher 344 rats at 15 months were treated daily with PM (1 g l−1 in drinking water) for 5 months and compared with the age-matched, untreated controls at 20 months. Pulsatile aortic pressure and flow signals were measured to perform the vascular impedance analysis. The anti-AGE antibody 6D12 was used to detect glycation-derived modification of aortic collagen, using protein blotting analysis. PM therapy attenuated the age-related increase in total peripheral resistance. An increase in wave transit time and aortic compliance by PM indicated that the drug improved aortic distensibility of the aged vasculature. This paralleled its reduction of AGE-collagen cross-links on aortas. Treatment of the old animals with PM also prevented the age-induced augmentation in vascular load imposed on the heart, as evidenced by an increased wave transit time and a decreased wave reflection factor. These findings suggest a partial role of PM in improving arterial mechanics by targeting the pathogenic formation of AGE-induced aortic collagen cross-links in old rats. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58530 |
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