Yamagishi S, Nakamura K, Matsui T, Inoue H
Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Med Hypotheses. 2007;69(2):338-40. doi: 10.1016/j.mehy.2006.11.054. Epub 2007 Feb 27.
Reducing sugars can react non-enzymatically with the amino groups of proteins to form reversible Schiff bases, and then Amadori products. These early glycation products undergo further complex reactions such as rearrangement, dehydration and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives termed "advanced glycation end products" (AGEs). The pathological role of the non-enzymatic glycation of proteins has become increasingly evident in various types of disorders such as diabetic vascular complications, neurodegenerative diseases, and melanoma growth and metastasis. Furthermore, there is a growing body of evidence that RAGE is a signal-transducing receptor for AGEs and that engagement of RAGE with AGEs evokes oxidative stress and vascular inflammation, thereby being involved in the AGE-related disorders. We have recently found that atorvastatin, a lipid-lowering agent decreases serum levels of AGEs in type 2 diabetic patients in a cholesterol-lowering independent manner. Further, we have shown that atorvastain blocks the AGE-signaling to C-reactive protein (CRP) expression in human hepatoma cells in vitro via anti-oxidative properties. These observations led us to speculate that atorvastatin could be a promising remedy for treating patients with AGE-related disorders. In this paper, we would like to propose the possible ways of testing our hypotheses. (1) Does atorvastatin treatment reduce the development and progression of diabetic vascular complications with normocholesterolemic patients? If the answer is yes, is this beneficial effect of atorvastatin superior to that of other cholesterol-lowering agents with equihypolipidemic properties? (2) Are these beneficial effects of atorvastain attributed to its AGE-lowing properties? Does the blockade by atorvastain of the AGE signaling pathway, in other words, the suppression of 8-hydroxydeoxyguanosine and CRP levels by atorvastatin treatment, contribute to its cardioprotective properties? (3) Does the treatment with atorvastatin decrease the incidence of neurodegenerative disorders such as Alzheimer's disease and/or prolong the survival of these patients? (4) How about the effects of atorvastatin on the incidence of malignant melanoma? These prospective studies will provide further valuable information whether the blockade by atorvastatin of the AGE formation or the AGE-downstream signaling could be clinically relevant.
还原糖可与蛋白质的氨基发生非酶反应，形成可逆的席夫碱，进而生成阿马多里产物。这些早期糖基化产物会经历进一步的复杂反应，如重排、脱水和缩合，变成不可逆交联的、异质的荧光衍生物，即“晚期糖基化终产物”（AGEs）。蛋白质非酶糖基化的病理作用在各种疾病中日益明显，如糖尿病血管并发症、神经退行性疾病以及黑色素瘤的生长和转移。此外，越来越多的证据表明，RAGE是AGEs的信号转导受体，RAGE与AGEs的结合会引发氧化应激和血管炎症，从而参与与AGE相关的疾病。我们最近发现，降血脂药物阿托伐他汀能以不依赖降低胆固醇的方式降低2型糖尿病患者血清中AGEs的水平。此外，我们还表明，阿托伐他汀在体外通过抗氧化特性阻断人肝癌细胞中AGE向C反应蛋白（CRP）表达的信号传导。这些观察结果使我们推测，阿托伐他汀可能是治疗与AGE相关疾病患者的一种有前景的药物。在本文中，我们想提出检验我们假设的可能方法。（1）阿托伐他汀治疗能否降低血脂正常的糖尿病患者血管并发症的发生和发展？如果答案是肯定的，阿托伐他汀的这种有益作用是否优于其他具有同等降血脂特性的降胆固醇药物？（2）阿托伐他汀的这些有益作用是否归因于其降低AGEs的特性？换句话说，阿托伐他汀对AGE信号通路的阻断，即阿托伐他汀治疗对8-羟基脱氧鸟苷和CRP水平的抑制，是否有助于其心脏保护特性？（3）阿托伐他汀治疗能否降低神经退行性疾病如阿尔茨海默病的发病率和/或延长这些患者的生存期？（4）阿托伐他汀对恶性黑色素瘤发病率有何影响？这些前瞻性研究将提供进一步有价值的信息，即阿托伐他汀对AGE形成或AGE下游信号传导的阻断在临床上是否具有相关性。
