Regulation of glycosaminoglycan structure and atherogenesis

Cardiovascular disease is the major cause of premature death in modern society, and its impact is increasing due to rising rates of obesity and type 2diabetes. Clinical studies based on targeting metabolic abnormalities and biomarkers demonstrate significant benefits, but always an element of disease remains which is resistant to treatment. Recent evidence has strongly implicated an early interaction of atherogenic lipoproteins with vascular matrix proteoglycans as the initiating step in atherogenesis. Expert commentary has pointed to the need for vascular directed therapies to provide reductions in the residual disease component. We propose that the regulation of synthesis and thus structure of glycosaminoglycans on proteoglycans provides a potential pathway to this reduction. We review existing evidence that the vascular synthesis of glycosaminoglycan chains can be regulated in a manner which reduces lipoprotein binding and the potential application of this strategy to attenuation of the current cardiovascular disease pandemic.Received 21 October 2003; received after revision 16 December 2003; accepted 29 December 2003     

Molecular basis of homocysteine toxicity in humans

Because of its similarity to the protein amino acid methionine, homocysteine (Hcy) can enter the protein biosynthetic apparatus. However, Hcy cannot complete the protein biosynthetic pathway and is edited by the conversion to Hcy-thiolactone, a reaction catalyzed by methionyl-transfer RNA synthetase in all organisms investigated, including human. Nitrosylation converts Hcy into a methionine analogue, S-nitroso-Hcy, which can substitute for methionine in protein synthesis in biological systems, including cultured human endothelial cells. In humans, Hcy-thiolactone modifies proteins posttranslationally by forming adducts in which Hcy is linked by amide bonds to -amino group of protein lysine residues (Hcy-N-Lys-protein). Levels of Hcy bound by amide or peptide linkages (Hcy-N-protein) in human plasma proteins are directly related to plasma total Hcy levels. Hcy-N-hemoglobin and Hcy-N-albumin constitute a major pool of Hcy in human blood, larger than total Hcy pool. Hcy-thiolactone and Hcy-thiolactone-hydrolyzing enzyme, a product of the PON1 gene, are present in human plasma. Modification with Hcy-thiolactone leads to protein damage and induces immune response. Autoantibodies that specifically recognize the Hcy-N-Lys-epitope on Hcy-thiolactone-modified proteins occur in humans. The ability of Hcy to interfere with protein biosynthesis, which causes protein damage, induces cell death and elicits immune response, is likely to contribute to the pathology of human disease.Received 30 May 2003; received after revision 21 July 2003; accepted 15 August 2003     

Cerivastatin: a cellular and molecular drug for the future?

The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market - the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future. Received 29 May 2002; received after revision 23 August 2002; accepted 26 August 2002 RID="*" ID="*"Corresponding author.     

低密度脂蛋白胆固醇、载脂蛋白B与颈动脉粥样硬化斑块的关系

目的 :观察颈动脉粥样硬化患者颈动脉的结构变化及粥样硬化斑块情况 ,研究低密度脂蛋白胆固醇 (L DL - C)、载脂蛋白 B(Apo B)与颈动脉粥样硬化斑块的关系。方法 :测定 10 0例患者空腹血中 L DL - C、Apo B浓度 ,并行颈动脉超声检查 ,测量斑块面积 ,并计算斑块积分和斑块指数。分别计算 L DL - C、Apo B与颈动脉粥样硬化斑块总积分的相关性。按 L DL - C/ Apo B比值分组 ,计算各组的平均斑块指数。结果 :L DL - C、Apo B与颈动脉粥样硬化斑块总积分之间均呈正相关 ,且二者的相关性相当 (r=0 .6 6 5 7,P<0 .0 1;r=0 .6 86 4 ,P<0 .0 1)。L DL - C/ Apo B<1.2 5组颈动脉粥样硬化斑块指数比 L DL - C/ Apo B>1.6 2组高 ,两者相比有显著性差异 (1.76± 0 .80 ,3.30± 1.4 6 ;P<0 .0 5 )。结论 :L DL - C、Apo B与颈动脉粥样硬化斑块的形成均有密切关系 ,其中 Apo B与颈动脉粥样硬化斑块的关系更密切     

同型半胱氨酸与心血管疾病

目的 :综述HCY致心血管疾病的发病机制和与动脉粥样硬化、冠心病的关系。方法 :光盘检索有关文献 ,归纳综合整理。结果 :同型半胱氨酸是心血管疾病的一个独立的危险因素 ,它能够通过损伤内皮细胞、促进血管平滑肌细胞的增殖、促使血小板受损以及作为一种基因毒性等方式引起心血管疾病的发生。结论 :心血管疾病的发生是多因素综合作用的结果     

双向凝胶电泳分析动脉粥样硬化大鼠心肌蛋白表达图谱

采用双相凝胶电泳分离大鼠冠状动脉总蛋白，胶态考马斯亮蓝G-250染色，GS-800凝胶扫描仪获取凝胶图像，并用PDQUEST软件分析，检测出2626个蛋白质斑点，并且得到不同条件下的蛋白质组的差异图谱，在相同的参数设置下，不同谱图间的匹配斑点数为1841，匹配率达70．1％以上，测量了凝胶蛋白斑点的在IEF、和SDS—PAGE方向上的位置偏差；对比分析了两种心肌组织的差异蛋白，发现33个蛋白质斑点只在正常大鼠心肌蛋白检测到表达；46个蛋白点在两种细胞中表达量上有显著变化，为从分子水平上理解心血管类疾病的发病机制，寻找防治药物和药物的构效关系的进一步研究开拓了新的途径，同时为深入研究AS的发病机制和药效研究提供参考数据。     

SPF 级FMMU 白化豚鼠基础生理指标的测定与比较

摘要: 目的测定与比较SPF 级FMMU 白化豚鼠血液指标、心率、颈总动脉压及心室压、脏器参数。方法取30 只雌雄各半、体质量250 ～ 300 g 范围内SPF 级FMMU 白化豚鼠,心脏采血后分别检测血常规、血生化及血气指标; 穿刺颈总动脉量取动脉压,辅助呼吸下开胸测定心室压; 解剖后称量各脏器质量。结果雄性与雌性豚鼠比较: 血液指标中,红细胞、血红蛋白、红细胞压积、谷草转氨酶、淀粉酶、胆固醇、二氧化碳总量、实际碳酸氢根、钠离子、总血红蛋白差异有显著性意义( P ＜ 0. 05 或P ＜ 0. 01) ; 颈总动脉舒张压、颈总动脉平均压、左心室舒张压、右心室收缩压、右心室平均压差异有显著性意义( P ＜ 0. 05 或P ＜ 0. 01) ; 体质量、脑质量差异以及脑垂体、肾上腺、左肾、右肾脏器系数差异有显著性意义( P ＜ 0. 05 或P ＜ 0. 01) 。结论不同性别的SPF 级FMMU 白化豚鼠血生理生化、血气、 颈总动脉压、心室压指标及脏器参数存在差异。     

冬季游泳运动对心血管系统保护机制的作用

冬季冰雪运动与心血管系统的益处尚不明确.通过对37名长年进行冬季游泳运动(CWS)的非职业运动员与对照健康者进行统计分析,记录一般情况,测定身体成分及血脂的实验室检查,比较2组发现,同型半胱氨酸和ApoB/ApoA-l比值有显著差异,在CWS组中呈降低趋势;CWS组的体重指数(BMI)和体脂率(BF％)较对照组明显升高...     

鼾症对颈动脉血管顺应性的影响

为了研究鼾症对动脉血管顺应性的影响，用两种状态下的实验SD鼠的颈动脉血管做离体灌注实验，一组在专用舱里生长，该组的鼠症状与鼾症症状相似，另一组在正常状态下生长．当实验对象符合实验条件后，从两组雄鼠身上分别取出它们的颈动脉进行离体灌注实验，采集所需的数据，算出所有老鼠的各个伸长比下的动脉血管顺应性值，并用统计学方法检测两组之间顺应性的差异，实验结果表明鼾症导致SD鼠颈动脉顺应性变大．     

ASA治疗对急性缺血性脑血管病微栓子及颈内动脉粥样硬化斑块的影响

目的以脑动脉系统微栓子及斑块为指标,探讨ASA(抗血小板药物、他汀类药物、抗高血压药物)治疗方案对急性脑梗死患者的治疗效果.方法选取经MRA或CTA证实、MES检出为阳性的急性脑梗死患者70例,分为对照组和治疗组,每组各35例.对照组给予改善循环和营养神经的药物治疗,治疗组在对照组基础上加ASA治疗,分别比较两组患者第3,6,9天微栓子(MES)数量和阳性率,同时比较斑块变化情况.结果 ASA治疗组比常规治疗组栓子下降率高,且随治疗时间的延长,其下降率之差增加,第9天时差异具有统计学意义(P0.05);ASA组斑块减小的更多.结论 ASA治疗可有效减小斑块的大小,减少微栓子的脱落,从而控制脑梗死的进展.