Kinnunen Paavo K J, Holopainen Juha M
Helsinki Biophysics & Biomembrane Group, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Trends Cardiovasc Med. 2002 Jan;12(1):37-42. doi: 10.1016/s1050-1738(01)00143-8.
Atherosclerosis is characterized by the accumulation in the arterial intima of mainly low-density lipoprotein (LDL)-derived lipids, together with apolipoprotein B-100 (apoB-100), the protein moiety of LDL. Recent studies indicate aggregation of LDL within the arterial wall to represent a critical step in the initiation of this disease. Aggregation of LDL has been further proposed to involve ceramide, the levels of which are elevated in atherosclerotic plaques as well as in LDL isolated from these lesions. Biophysical studies have shown ceramide to have a pronounced tendency for self-aggregation, presumably driven by intermolecular hydrogen bonding. Importantly, the segregated ceramide-enriched lipid phases have high melting temperatures and are in a gel state at 37 degrees C. The plasma levels of sphingomyelin, which upon enzymatic hydrolysis by sphingomyelinase (SMase) yields ceramide, have been shown to correlate with the severity of coronary heart disease. The formation of ceramide from sphingomyelin could thus represent a critical step in atherosclerosis. We recently showed that LDL itself possesses SMase activity. Moreover, sequence analogy with bacterial enzymes suggests that this activity may be intrinsic to apoB-100. Possible physiological role of this activity is uncertain, yet could be involved in nonreceptor-mediated endocytotic entry of LDL into cells. Importantly, it also opens a possible mechanistic link between elevated plasma levels of LDL, apoptosis (programmed cell death), and atherosclerosis.
动脉粥样硬化的特征是动脉内膜中主要堆积低密度脂蛋白（LDL）衍生的脂质，以及载脂蛋白B-100（apoB-100），即LDL的蛋白质部分。最近的研究表明，LDL在动脉壁内的聚集是该疾病起始的关键步骤。进一步的研究提出，LDL的聚集涉及神经酰胺，在动脉粥样硬化斑块以及从这些病变中分离出的LDL中，神经酰胺的水平都会升高。生物物理学研究表明，神经酰胺具有明显的自我聚集倾向，可能是由分子间氢键驱动的。重要的是，分离出的富含神经酰胺的脂质相具有较高的熔点，在37摄氏度时处于凝胶状态。血浆中鞘磷脂的水平，经鞘磷脂酶（SMase）酶促水解后会产生神经酰胺，已被证明与冠心病的严重程度相关。因此，鞘磷脂形成神经酰胺可能是动脉粥样硬化的关键步骤。我们最近发现LDL本身具有SMase活性。此外，与细菌酶的序列相似性表明，这种活性可能是apoB-100所固有的。这种活性的可能生理作用尚不确定，但可能参与LDL通过非受体介导的内吞作用进入细胞的过程。重要的是，它还揭示了血浆中LDL水平升高、细胞凋亡（程序性细胞死亡）和动脉粥样硬化之间可能的机制联系。
