Atorvastatin可改善streptozotocin所誘發糖尿病鼠之動脈硬化及心室肥厚

Abstract

研究背景與目的：高血糖與血脂異常為糖尿病患者共有的特徵，這不僅會增加患者體內的氧化壓力，亦會降低一氧化氮之生物可利用率，因而造成內皮細胞功能異常。目前已證實，內皮細胞功能異常在糖尿病患者形成心血管疾病的病理過程中，佔有重要的影響力。Statins是3-羥基-3-甲基戊二醯輔酶A (3-hydroxyl-3-methylglutaryl coenzyme A, HMG-CoA) 還原酶的抑制劑，能夠有效降低血中脂質，故常用來作為預防心血管疾病的用藥；此外，statins也可以透過非膽固醇途徑或稱為多效作用，降低心血管事件發生的機率。文獻指出，使用低劑量的atorvastatin (Ator) 可在不改變脂質含量的情況下，造成氧化壓力的降低。本實驗以此為基礎，在不影響總膽固醇含量且能夠降低氧化壓力的狀態下，評估低劑量Ator對streptozotocin (STZ) 所誘發糖尿病鼠之動脈系統物理性質的影響。 研究方法：雄性Wistar 大白鼠於兩個月大時，以尾靜脈注射每公斤55毫克（55 mg kg-1）的STZ以誘發糖尿病的產生。待大鼠出現高血糖症狀後，給予餵食組每日灌食每公斤10毫克（10 mg kg-1）的Ator，連續給藥六週，並與同齡未給藥之糖尿病控制組作對照。在升主動脈處，使用高傳真Millar導管與電磁血流探頭分別測得脈態血壓與血流訊號，經主動脈輸入阻抗頻譜分析以探討動脈系統的物理性質與脈波的反射現象。每隻動物在取得所需訊號之後，隨即犧牲動物以採集血液與組織樣本，進行游離脂肪酸、總膽固醇以及丙二醛/硫代巴比妥酸反應物質的分析。 結果：本實驗觀察到低劑量的Ator能夠顯著降低糖尿病鼠血漿中游離脂肪酸與丙二醛含量，但不會對總膽固醇造成影響。與糖尿病控制組相較，餵食Ator的糖尿病鼠在主動脈血壓參數、基礎心跳速率、心輸出量以及周邊總阻力皆無顯著差異。然而，Ator會增加糖尿病鼠之主動脈特徵阻抗，但對主動脈容積度卻無影響。而在脈波反射現象方面，Ator對於波傳輸時間以及波反射係數分別有著15.4% 的增加 (P<0.05)，以及33.5% 的減低 (P<0.001)，顯示Ator能夠有效降低糖尿病所引起之左心室收縮負荷的增加，以改善糖尿病所導致之心室肥厚的現象，此結果可由左心室重量對體重的比值有顯著下降得到證實。 結論：給予STZ－糖尿病鼠低劑量的Ator，能夠在不影響總膽固醇的情況下，降低脂質氧化物丙二醛，並顯著地改善糖尿病所導致的主動脈硬化以及左心室肥厚的現象。

Background and purpose: Patients with diabetes mellitus have the characteristics of hyperglycemia and dyslipidemia, leading to an increase in oxidative stress and a decrease in nitric oxide (NO) bioavailability. These can cause endothelial dysfunction, which is an important process in the pathogenesis of cardiovascular diseases in diabetes. Statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are often utilized in the prevention of cardiovascular diseases by their efficacy at lowering lipid levels. Statins may also reduce the incidence of cardiovascular events by their non-lipid or pleiotropic effects. It has been reported that low-dose therapy by atorvastatin (Ator), one of currently available statins, did not alter the lipid profile but led to a reduction in oxidative stress. The aim of the current study was to determine whether such a low-dose Ator could produce benefits on the mechanical properties of arterial system through its decrease of oxidative stress in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetes was induced in male Wistar rats at two monthes by a single tail vein injection of STZ 55 mg kg-1. After induction of hyperglycemia, the diabetic rats daily treated with Ator 10 mg kg-1 for six weeks by oral gavage were compared with the untreated age-matched diabetic controls. Pulsatile aortic pressure and flow signals were measured to describe the physical properties of the arterial system along with the pulse wave reflection phenomena. At the end of the experiment, blood and tissue samples were collected to obtain the plasma levels of free fatty acid (FFA), total cholesterol and the plasma and tissue levels of malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS). Results: In the absence of any significant changes in total cholesterol, the low dosage of Ator used in this study lowered the plasma levels of free fatty acid and the plasma and tissue levels of MDA/TBARS in diabetes. After exposure to Ator, the STZ-induced diabetic rats showed no significant changes in aortic pressure profile, basal heart rate, cardiac output and total peripheral resistance. Meanwhile, aortic characteristic impedance but not aortic compliance increased markedly in response to Ator therapy in the diabetic animals. As for wave reflection phenomena, Ator exhibited significant changes in both wave transit time by +15.4% (P<0.05) and wave reflection factor by -33.5% (P<0.001). These suggested that Ator may attenuate the diabetes-induced augmentation in systolic load imposed on the heart. The decline in systolic load by Ator treatment could be responsible for the prevention of the diabetes-related cardiac hypertrophy, as manifested by the diminished ratio of left ventricular weight to body weight. Conclusion: Our data suggest that low-lose Ator therapy may attenuate the diabetes-induced aortic stiffening and cardiac hypertrophy, possibility through its decrease of lipid oxidation-derived MDA/TBARS but not related to the total cholesterol-lowering effects of Ator in the STZ-diabetic rats.