Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction
Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction
复制标题
DOI：
10.1161/atvbaha.113.301933
复制
发表时间：
2013-09-01
影响因子：
8.7
通讯作者：
Bereziat, Veronique
中科院分区：
文献类型：
--
作者：
Bidault, Guillaume;Garcia, Marie;Bereziat, Veronique
目的：编码a型纤层蛋白的LMNA的一些突变导致了dunnigan型家族性部分脂肪营养不良（FPLD2），并改变了脂肪分布和代谢。这些患者早期和严重心血管结局的高患病率表明，除了代谢危险因素外，fpld2相关的LMNA突变可能对血管壁细胞有直接作用。方法与结果-我们分析了19例年龄在bb0 ~ 30岁的FPLD2患者的心血管表型，并通过LMNA p. r4882杂合替换，以及p.R482W-prelamin-A在人冠状动脉内皮细胞中过表达的影响。在68%的FPLD2患者中，临床心血管事件证明了早期动脉粥样硬化，在大多数病例中发生在45岁之前。在转导的内皮细胞中，外源性野生型prelamin- a被正确加工和定位，而p.R482W-prelamin-A在核膜处异常积累。患者的成纤维细胞也表现出明显的核膜分布，同时层前蛋白a成熟率降低。只有p.R482W-prelamin-A诱导内皮功能障碍，一氧化氮生成减少，外周血单个核细胞内皮粘附增加，细胞衰老。p.R482W-prelamin-A还能诱导氧化应激、DNA损伤和炎症。用普伐他汀或抗氧化剂治疗内皮细胞可防止这些改变，普伐他汀可抑制prelamin-A法尼化。此外，普伐他汀允许内皮细胞核内p.R482W-prelamin-A的正确重新定位。这些数据表明，法酰化的p.R482W-prelamin-A在核膜上的积累是一种毒性事件，导致细胞氧化应激和内皮功能障碍。结论- lmna p.R482突变与FPLD2相关，对内皮细胞具有直接的促动脉粥样硬化作用，可能导致患者早期动脉粥样硬化。
Objective-Some mutations in LMNA, encoding A-type lamins, are responsible for Dunnigan-type-familial partial lipodystrophy (FPLD2), with altered fat distribution and metabolism. The high prevalence of early and severe cardiovascular outcomes in these patients suggests that, in addition to metabolic risk factors, FPLD2-associated LMNA mutations could have a direct role on the vascular wall cells.Approach and Results-We analyzed the cardiovascular phenotype of 19 FPLD2 patients aged >30 years with LMNA p.R482 heterozygous substitutions, and the effects of p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. In 68% of FPLD2 patients, early atherosclerosis was attested by clinical cardiovascular events, occurring before the age of 45 in most cases. In transduced endothelial cells, exogenous wild-type-prelamin-A was correctly processed and localized, whereas p.R482W-prelamin-A accumulated abnormally at the nuclear envelope. Patients' fibroblasts also showed a predominant nuclear envelope distribution with a decreased rate of prelamin-A maturation. Only p.R482W-prelamin-A induced endothelial dysfunction, with decreased production of NO, increased endothelial adhesion of peripheral blood mononuclear cells, and cellular senescence. p.R482W-prelamin-A also induced oxidative stress, DNA damages, and inflammation. These alterations were prevented by treatment of endothelial cells with pravastatin, which inhibits prelamin-A farnesylation, or with antioxidants. In addition, pravastatin allowed the correct relocalization of p.R482W-prelamin-A within the endothelial cell nucleus. These data suggest that farnesylated p.R482W-prelamin-A accumulation at the nuclear envelope is a toxic event, leading to cellular oxidative stress and endothelial dysfunction.Conclusions-LMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients' early atherosclerosis.