Singh Vishal, Tiwari Rajiv L, Dikshit Madhu, Barthwal Manoj K
Division of Pharmacology, Central Drug Research Institute, India.
Curr Vasc Pharmacol. 2009 Jan;7(1):75-109. doi: 10.2174/157016109787354097.
The recent failure of candidate drugs like cholesterol ester transfer protein (CETP) and acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors calls for a revised approach for screening anti-atherosclerotic drugs and development of new models of atherosclerosis. For this it is important to understand the mechanism of the disease in a particular model. Models simultaneously showing hyperlipidemia, inflammation and associated complications of diabetes and hypertension will serve the purpose better as they mimic the actual clinical condition. Besides this, analyzing candidate molecules in vivo, in vitro and at various levels of atherosclerosis progression is important. Models based on various cells and process involved in atherosclerosis should be used for screening candidate molecules. The challenge lies in bridging the gap between genetically friendly small animal and human-like bigger animal models. Sequencing of the mouse and human genome, development of a single nucleotide polymorphism (SNP) database and in silico quantitative trait loci (QTL) linkage analysis may enhance the understanding of atherosclerosis and help develop new therapeutic targets.
近期，诸如胆固醇酯转运蛋白（CETP）抑制剂和酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂等候选药物的研发失败，这就需要修订抗动脉粥样硬化药物的筛选方法，并开发新的动脉粥样硬化模型。为此，了解特定模型中疾病的发病机制至关重要。同时表现出高脂血症、炎症以及糖尿病和高血压相关并发症的模型将更符合要求，因为它们模拟了实际临床情况。除此之外，在体内、体外以及动脉粥样硬化进展的各个阶段分析候选分子也很重要。基于参与动脉粥样硬化的各种细胞和过程构建的模型应用于筛选候选分子。挑战在于弥合基因友好型小动物模型与类人大型动物模型之间的差距。小鼠和人类基因组测序、单核苷酸多态性（SNP）数据库的开发以及计算机模拟定量性状位点（QTL）连锁分析，可能会增进对动脉粥样硬化的理解，并有助于开发新的治疗靶点。
