UPMC Univ Paris 06, UMR_S938, Paris, France.
Arterioscler Thromb Vasc Biol. 2013 Sep;33(9):2162-71. doi: 10.1161/ATVBAHA.113.301933. Epub 2013 Jul 11.
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.
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.
LMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients' early atherosclerosis.
编码 A 型核纤层蛋白的 LMNA 中的某些突变导致邓尼根型家族性部分脂肪营养不良（FPLD2），其特征为脂肪分布和代谢改变。这些患者心血管不良事件的高发生率提示，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。
我们分析了 19 名年龄 >30 岁、携带 LMNA p.R482 杂合替换的 FPLD2 患者的心血管表型，并研究了人冠状动脉内皮细胞中 p.R482W 前核纤层蛋白-A 过表达的作用。在 68%的 FPLD2 患者中，通过临床心血管事件证实了早发动脉粥样硬化，大多数患者在 45 岁之前发生。在转导的内皮细胞中，外源性野生型前核纤层蛋白-A 被正确加工和定位，而 p.R482W 前核纤层蛋白-A 异常积累在核膜上。患者的成纤维细胞也显示出以核膜为主的分布，前核纤层蛋白-A 成熟率降低。只有 p.R482W 前核纤层蛋白-A 诱导内皮功能障碍，导致 NO 产生减少、外周血单核细胞内皮黏附增加和细胞衰老。p.R482W 前核纤层蛋白-A 还诱导氧化应激、DNA 损伤和炎症。这些改变可以通过用抑制前核纤层蛋白-A 法尼基化的普伐他汀或抗氧化剂处理内皮细胞来预防。此外，普伐他汀允许 p.R482W 前核纤层蛋白-A 在内皮细胞核内的正确重新定位。这些数据表明，核膜上堆积的法尼基化 p.R482W 前核纤层蛋白-A 是一种毒性事件，导致细胞氧化应激和内皮功能障碍。
导致 FPLD2 的 LMNA p.R482 突变在内皮细胞中具有直接的促动脉粥样硬化作用，这可能导致患者的早发动脉粥样硬化。
