OP8: Early atherosclerosis in Familial Partial Lipodystrophy of the Dunnigan-type: Endothelial cell dysfunction induced by p.R482W lamin-A

Abstract

Some mutations in LMNA, encoding A-type lamins, are responsible for lipodystrophic syndromes, which present features of severe metabolic syndrome. p.R482 substitutions lead to the Dunnigan familial partial lipodystrophy (FPLD2) while the p.L92F mutation gives a phenotype of metabolic laminopathy (ML). FPLD2 has been associated with precocious atherosclerosis. We analyzed the cardiovascular phenotype of nineteen patients with FPLD2 and a patient with ML (LMNA p.L92F). Despite similar metabolic alterations, FPLD2 patients, but not the ML patient, presented early atherosclerosis. We then studied the effects of wild-type or mutated p.R482W and p.L92F-prelamin-A overexpression on primary cultured human coronary endothelial cells (HCAECs). Although both mutations led to defects in prelamin-A maturation, only p.R482W-prelamin-A was predominantly distributed to the nuclear envelope, in favor of its persistent farnesylation. p.R482W but not wild-type or p.L92F-prelamin-A overexpression led to endothelial dysfunction, with decreased expression of endothelial nitric oxide synthase, increased inflammation, and increased endothelial adhesion of peripheral blood mononuclear cells. p.R482W-prelamin-A also induced oxidative stress, increased DNA double-strand breaks and cellular senescence. In vitro pravastatin treatment, which inhibits prelamin-A farnesylation, decreased p.R482W-prelamin-A association to the nuclear envelope, oxidative stress and inflammation. In addition, anti-oxidants decreased inflammation and DNA double-strand breaks occurrence, suggesting that farnesylated p.R482W-prelamin-A induced oxidative stress which resulted in endothelial dysfunction. FPLD2-associated p.R482W but not ML-associated p.L92F lamin-A mutation resulted in farnesylatedprelamin- A accumulation that induced endothelial dysfunction in vitro. These observations suggest that LMNA p.R482 mutations have a direct pro-atherogenic role, contributing to the early occurrence of atherosclerosis in FPLD2.