Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA.
Cell Mol Life Sci. 2012 Oct;69(20):3361-80. doi: 10.1007/s00018-012-0982-9. Epub 2012 Apr 11.
Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors.
心血管疾病是西方世界发病率和死亡率的首要原因。动脉粥样硬化继之以血栓形成（动脉血栓形成）是大多数心肌、脑和外周血管事件的病理过程。动脉血栓形成是一种复杂的异质炎症过程，涉及许多细胞类型（包括血管平滑肌细胞、内皮细胞、巨噬细胞和血小板）和过程（包括迁移、增殖和激活）之间的相互作用。尽管最近的许多研究使用敲除小鼠和人类遗传研究（GWAS 和候选方法）确定了直接参与这些过程的基因和蛋白质，提供了丰富的知识，但传统的心血管危险因素（高脂血症、高血压、吸烟、糖尿病、性别和年龄）仍然是疾病最有用的预测因素。类二十烷酸（花生四烯酸和其他必需脂肪酸的 20 碳多不饱和脂肪酸衍生物）作为心血管疾病过程的重要调节剂而出现。间接调节这些信号的药物，包括 COX-1/COX-2 抑制剂，已被证明在动脉血栓形成过程中发挥主要作用。然而，由于它们的作用的复杂性和受相反的类二十烷酸信号的调节，导致缺乏针对类二十烷酸受体本身的治疗方法。随着我们对类二十烷酸受体的结构、信号和功能的理解的提高，这种情况可能会发生变化。事实上，从类二十烷酸受体的功能失调的自然发生突变的特征中出现了一个重大进展。鉴于风险因素的已证实和持续重要性，我们选择关注类二十烷酸与心血管风险因素之间的关系。
