Yamagishi S, Matsui T, Nakamura K
Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Med Hypotheses. 2007;68(5):1096-8. doi: 10.1016/j.mehy.2006.07.059. Epub 2006 Nov 13.
Vascular calcification is a common feature in advanced atherosclerosis and also a predictor of future cardiovascular events such as unstable angina and myocardial infarction, especially in diabetes. There is a growing body of evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate in diabetes, exist within atherosclerotic lesions, thereby being implicated in the pathogenesis of accelerated atherosclerosis in diabetes. Indeed, we have previously shown that AGE - their receptor (RAGE) interaction could induce angiogenesis through autocrine production of vascular endothelial growth factor, suggesting its role for plaque formation and enlargement in diabetes. Furthermore, we have found that AGEs have the ability to induce the osteoblatic differentiation of pericytes, thus contributing to the development of vascular calcification as well. These observations suggest that the inhibition of AGE formation or blockade of the downstream signaling of RAGE may be a novel therapeutic target for the inhibition of vascular calcification in diabetic atherosclerosis. Since we, along with others, have shown that nifedipine inhibits glycation of low-density lipoprotein in vitro and blocks the AGE-induced RAGE expression in endothelial cells through its anti-oxidative properties, nifedipine could inhibit vascular calcification by blocking the AGE formation or the downstream signaling in diabetes. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment slow down the progression of coronary calcification in diabetic patients? If the answer is yes, is this beneficial effect of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease expression levels of AGEs and RAGE in diabetic atherosclerosis? Is the unique effect of nifedipine on vascular calcification correlated with its AGE or RAGE-suppressing properties? These prospective studies will provide further valuable information whether nifedipine could prevent vascular calcification in diabetic atherosclerosis by blockade the AGE-RAGE signaling in vascular wall cells.
血管钙化是晚期动脉粥样硬化的常见特征，也是未来心血管事件（如不稳定型心绞痛和心肌梗死）的预测指标，在糖尿病患者中尤为如此。越来越多的证据表明，晚期糖基化终产物（AGEs）是糖尿病中加速形成的衰老大分子蛋白衍生物，存在于动脉粥样硬化病变中，因此与糖尿病中加速动脉粥样硬化的发病机制有关。事实上，我们之前已经表明，AGE与其受体（RAGE）的相互作用可通过自分泌血管内皮生长因子诱导血管生成，提示其在糖尿病斑块形成和增大中的作用。此外，我们发现AGEs有能力诱导周细胞向成骨细胞分化，从而也促进了血管钙化的发展。这些观察结果表明，抑制AGE形成或阻断RAGE的下游信号可能是抑制糖尿病动脉粥样硬化中血管钙化的新治疗靶点。由于我们和其他人已经表明硝苯地平在体外可抑制低密度脂蛋白的糖基化，并通过其抗氧化特性阻断AGE诱导的内皮细胞中RAGE的表达，硝苯地平可能通过阻断糖尿病中的AGE形成或下游信号来抑制血管钙化。在本文中，我们想提出检验我们假设的可能方法。硝苯地平治疗是否能减缓糖尿病患者冠状动脉钙化的进展？如果答案是肯定的，硝苯地平的这种有益作用是否优于其他具有同等降压特性的二氢吡啶类药物？硝苯地平治疗是否能降低糖尿病动脉粥样硬化中AGEs和RAGE的表达水平？硝苯地平对血管钙化的独特作用是否与其抑制AGE或RAGE的特性相关？这些前瞻性研究将提供进一步有价值的信息，即硝苯地平是否可通过阻断血管壁细胞中的AGE-RAGE信号来预防糖尿病动脉粥样硬化中的血管钙化。
