Deepa P R, Varalakshmi P
Department of Medical Biochemistry, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600 113, India.
Int J Cardiol. 2006 Jan 26;106(3):338-47. doi: 10.1016/j.ijcard.2005.02.012.
In the hypercholesterolemic state, the net result of combined oxidative and nitrosative stress is a pro-inflammatory phenotype that is manifested as increased adhesion molecule expression, enhanced leucocyte trafficking, and increased vascular permeability. The present work explores the inflammatory aspects of hypercholesterolemic atherogenesis, and also evaluates the role of a low-molecular-weight heparin derivative (LMWH), Certoparin, on a biochemical basis.
Two groups of male Wistar rats were fed an atherogenic diet (normal rat chow plus 4% cholesterol, 1% cholic acid and 0.5% thiouracil-CCT diet) for 2 weeks. While one was left untreated, the other was administered LMWH (300 microg/day/rat commencing on day 8 and continued for a week). Increased concentrations of plasma C-reactive protein and fibrinogen and cardiac TNF-alpha indicated severe inflammation in the atherogenic diet fed rats. In comparison, these biochemical indices of inflammation diminished significantly in the LMWH treated group (p < 0.001). Significant depletion of thiols, along with accentuated activities of the glutathione metabolising was observed in the cardiac and hepatic tissues of the untreated atherogenic rats, indicating heightened oxidative response. Tissue damage was marked by elevated levels of plasma and tissue hexose, hexosamine, hexuronic acid and sialic acid, which were reversed towards normalcy on LMWH administration. The activities of lysosomal enzymes (N-acetyl glucosaminidase, beta-glucuronidase, beta-galactosaminidase and cathepsin-D) showed a marked increase in the CCT-diet fed rats, while LMWH treated rats showed normal activities (p < 0.001). The osmotic fragility test revealed that the untreated hyperlipidemic rat erythrocytes were significantly fragile at high salt concentrations, while the response was normalized in the LMWH treated group (p < 0.05). Further, hypercholesterolemia induced downregulation of physiological nitric oxide levels was corrected upon treatment with heparin-derivative.
The results of this work highlight the inflammatory changes in atherogenic conditions and that the low-molecular-weight heparin derivative affords substantial protection.
在高胆固醇血症状态下，氧化应激和亚硝化应激共同作用的最终结果是产生一种促炎表型，表现为黏附分子表达增加、白细胞运输增强和血管通透性增加。本研究探讨了高胆固醇血症动脉粥样硬化形成过程中的炎症方面，并在生化基础上评估了低分子量肝素衍生物（LMWH）——克赛®的作用。
两组雄性Wistar大鼠喂食致动脉粥样硬化饮食（正常大鼠饲料加4%胆固醇、1%胆酸和0.5%硫脲——CCT饮食）2周。一组不进行处理，另一组给予LMWH（从第8天开始，300微克/天/只大鼠，持续一周）。血浆C反应蛋白和纤维蛋白原浓度升高以及心脏肿瘤坏死因子-α表明喂食致动脉粥样硬化饮食的大鼠存在严重炎症。相比之下，这些炎症生化指标在LMWH处理组中显著降低（p<0.001）。在未处理的致动脉粥样硬化大鼠的心脏和肝脏组织中观察到硫醇显著消耗，同时谷胱甘肽代谢活性增强，表明氧化反应增强。血浆和组织中己糖、氨基己糖、己糖醛酸和唾液酸水平升高表明组织损伤，给予LMWH后这些指标恢复正常。溶酶体酶（N-乙酰葡糖胺酶、β-葡糖醛酸酶、β-半乳糖胺酶和组织蛋白酶-D）的活性在喂食CCT饮食的大鼠中显著增加，而LMWH处理的大鼠活性正常（p<0.001）。渗透脆性试验显示，未处理的高脂血症大鼠红细胞在高盐浓度下显著脆弱，而LMWH处理组的反应恢复正常（p<0.05）。此外，用肝素衍生物治疗后，高胆固醇血症诱导的生理一氧化氮水平下调得到纠正。
本研究结果突出了致动脉粥样硬化条件下的炎症变化，且低分子量肝素衍生物提供了实质性保护。
