Omi Hitoshi, Okayama Naotsuka, Shimizu Manabu, Fukutomi Tatsuya, Nakamura Atsushi, Imaeda Kenro, Okouchi Masahiro, Itoh Makoto
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Microvasc Res. 2004 Sep;68(2):119-25. doi: 10.1016/j.mvr.2004.05.002.
Endothelial-neutrophil adhesion is crucial for vascular injury, the major cause of diabetic vascular complications. On the other hand, platelet aggregation inhibitors, frequently used for diabetic patients with intermittent claudication, have been shown to decrease the incidence of atherosclerosis-mediated diseases (acute myocardial infarction and stroke). However, whether these agents act directly on the endothelial reactions to hyperglycemia remains unclear. Therefore, we examined their direct effects on endothelial-neutrophil adhesion and expression of endothelial adhesion molecules induced by high glucose.
After human endothelial cells were cultured in high glucose medium, neutrophils from healthy volunteers were added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring their myeloperoxidase (MPO) activities, and surface expression of endothelial adhesion molecules was determined with an enzyme immunoassay. Of the platelet aggregation inhibitors tested, only cilostazol significantly attenuated the adhesion through decreasing expression of intercellular adhesion molecule-1 (ICAM-1) and P-selectin. In addition, nitric oxide (NO) synthase inhibitors reduced the inhibitory effects of cilostazol, but a protein kinase C (PKC) activator did not.
Cilostazol may act directly on endothelial cells to inhibit expression of adhesion molecules and neutrophil adhesion induced by high glucose through increasing NO production.
内皮细胞与中性粒细胞的黏附对于血管损伤至关重要，而血管损伤是糖尿病血管并发症的主要原因。另一方面，常用于患有间歇性跛行的糖尿病患者的血小板聚集抑制剂已被证明可降低动脉粥样硬化介导疾病（急性心肌梗死和中风）的发生率。然而，这些药物是否直接作用于内皮细胞对高血糖的反应仍不清楚。因此，我们研究了它们对高糖诱导的内皮细胞与中性粒细胞黏附以及内皮黏附分子表达的直接影响。
将人内皮细胞在高糖培养基中培养后，加入健康志愿者的中性粒细胞并使其黏附30分钟。通过测量髓过氧化物酶（MPO）活性对黏附的中性粒细胞进行定量，并采用酶免疫测定法测定内皮黏附分子的表面表达。在所测试的血小板聚集抑制剂中，只有西洛他唑通过降低细胞间黏附分子-1（ICAM-1）和P-选择素的表达，显著减弱了黏附。此外，一氧化氮（NO）合酶抑制剂降低了西洛他唑的抑制作用，但蛋白激酶C（PKC）激活剂则没有。
西洛他唑可能直接作用于内皮细胞，通过增加NO生成来抑制高糖诱导的黏附分子表达和中性粒细胞黏附。
