Renier Geneviève, Mamputu Jean-Claude, Serri Omar
CHUM Research Centre, Metabolic Unit, Notre-Dame Hospital, Montreal Quebec, Canada.
Metabolism. 2003 Aug;52(8 Suppl 1):13-8. doi: 10.1016/s0026-0495(03)00212-9.
Atherosclerotic cardiovascular disease is the leading cause of premature death in patients with diabetes. Atherosclerosis is a chronic immune-mediated disease, the initiation, progression, and destabilization of which is driven and regulated by inflammatory cells. One critical event in the initiation of this vascular inflammatory disease is the adhesion of leukocytes to the activated endothelium and their migration into the vessel wall. These processes are mediated by the upregulation of adhesion molecules on endothelial cells (ECs) and an increased expression in the vascular wall of chemotactic factors to leukocytes. Monocyte binding to ECs is increased in diabetes. One major determinant of this alteration could be oxidative stress. Given the free-radical scavenging activity of gliclazide, we determined the ex vivo and in vitro effects of this drug on human monocyte binding to ECs and the molecular mechanisms involved in this effect. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes normalizes the levels of plasma lipid peroxides and monocyte adhesion in these subjects. Gliclazide (10 microg/mL) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to ECs in vitro. The inhibitory effect of this drug on AGE-induced monocyte adhesion involves a reduction in EC adhesion molecule expression and inhibition of nuclear factor kappaB (NF-kappaB) activation. In addition, gliclazide inhibits oxLDL-induced monocyte adhesion to cultured human aortic vascular smooth muscle cells (HASMCs) in vitro and reduces the production of monocyte chemotactic protein-1 (MCP-1) by these cells. Taken collectively, these results show that gliclazide, at concentrations in the therapeutic range, inhibits ex vivo and in vitro monocyte adhesiveness to vascular cells. By doing so, this drug could reduce monocyte recruitment into the vessel wall and thereby contribute to attenuating the sustained inflammatory process that occurs in the atherosclerotic plaque. These findings suggest that treatment of diabetic patients with this drug may prevent or retard the development of vasculopathies associated with diabetes.
动脉粥样硬化性心血管疾病是糖尿病患者过早死亡的主要原因。动脉粥样硬化是一种慢性免疫介导性疾病，其起始、进展和失稳由炎症细胞驱动和调节。这种血管炎症性疾病起始过程中的一个关键事件是白细胞黏附于活化的内皮细胞并迁移至血管壁。这些过程由内皮细胞（ECs）上黏附分子的上调以及血管壁中白细胞趋化因子表达的增加介导。糖尿病患者中单核细胞与ECs的结合增加。这种改变的一个主要决定因素可能是氧化应激。鉴于格列齐特的自由基清除活性，我们确定了该药物对人单核细胞与ECs结合的体内外效应以及参与此效应的分子机制。我们的结果表明，对2型糖尿病患者短期给予格列齐特可使这些受试者的血浆脂质过氧化物水平和单核细胞黏附正常化。格列齐特（10微克/毫升）在体外也可减少氧化型低密度脂蛋白（oxLDL）和晚期糖基化终产物（AGE）诱导的单核细胞与ECs的黏附。该药物对AGE诱导的单核细胞黏附的抑制作用涉及EC黏附分子表达的降低和核因子κB（NF-κB）激活的抑制。此外，格列齐特在体外可抑制oxLDL诱导的单核细胞与培养的人主动脉血管平滑肌细胞（HASMCs）的黏附，并减少这些细胞产生单核细胞趋化蛋白-1（MCP-1）。总体而言，这些结果表明，治疗范围内浓度的格列齐特可抑制体内外单核细胞对血管细胞的黏附性。通过这样做，该药物可减少单核细胞募集至血管壁，从而有助于减轻动脉粥样硬化斑块中发生的持续炎症过程。这些发现表明，用该药物治疗糖尿病患者可能预防或延缓与糖尿病相关的血管病变的发展。
