Heart Rhythm Management Centre UZB, Brussels, Belgium.
PLoS One. 2012;7(4):e36373. doi: 10.1371/journal.pone.0036373. Epub 2012 Apr 30.
Fabry disease (FD) is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA) resulting in the accumulation of globotriaosylsphingosine (Gb3) in a variety of tissues. While GLA deficiency was always considered as the fulcrum of the disease, recent attention shifted towards studying the mechanisms through which Gb3 accumulation in vascular cells leads to endothelial dysfunction and eventually multiorgan failure. In addition to the well-described macrovascular disease, FD is also characterized by abnormalities of microvascular function, which have been demonstrated by measurements of myocardial blood flow and coronary flow reserve. To date, the relative importance of Gb3 accumulation versus GLA deficiency in causing endothelial dysfunction is not fully understood; furthermore, its differential effects on cardiac micro- and macrovascular endothelial cells are not known.
In order to assess the effects of Gb3 accumulation versus GLA deficiency, human macro- and microvascular cardiac endothelial cells (ECs) were incubated with Gb3 or silenced by siRNA to GLA. Gb3 loading caused deregulation of several key endothelial pathways such as eNOS, iNOS, COX-1 and COX-2, while GLA silencing showed no effects. Cardiac microvascular ECs showed a greater susceptibility to Gb3 loading as compared to macrovascular ECs.
Deregulation of key endothelial pathways as observed in FD vasculopathy is likely caused by intracellular Gb3 accumulation rather than deficiency of GLA. Human microvascular ECs, as opposed to macrovascular ECs, seem to be affected earlier and more severely by Gb3 accumulation and this notion may prove fundamental for future progresses in early diagnosis and management of FD patients.
法布里病（FD）是由于溶酶体酶α-半乳糖苷酶 A（GLA）缺乏导致糖鞘脂神经酰胺三己糖苷（Gb3）在多种组织中积累引起的。虽然 GLA 缺乏一直被认为是疾病的关键，但最近的研究重点已转移到研究 Gb3 在血管细胞中积累导致内皮功能障碍并最终导致多器官衰竭的机制。除了众所周知的大血管疾病外，FD 还表现为微血管功能异常，这可以通过测量心肌血流和冠状动脉血流储备来证实。迄今为止，Gb3 积累与 GLA 缺乏导致内皮功能障碍的相对重要性尚未完全清楚；此外，其对心脏微血管和大血管内皮细胞的不同影响尚不清楚。
为了评估 Gb3 积累与 GLA 缺乏的影响，用 Gb3 孵育人心脏大、微血管内皮细胞（ECs）或用 siRNA 沉默 GLA。Gb3 负荷导致几个关键的内皮途径失调，如 eNOS、iNOS、COX-1 和 COX-2，而 GLA 沉默则没有影响。与大血管 ECs 相比，心脏微血管 ECs 对 Gb3 负荷的敏感性更高。
FD 血管病变中观察到的关键内皮途径失调可能是由细胞内 Gb3 积累引起的，而不是 GLA 缺乏。与大血管 ECs 相比，人微血管 ECs 似乎更容易受到 Gb3 积累的早期和更严重的影响，这一概念可能对 FD 患者的早期诊断和治疗的未来进展具有重要意义。
