LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation

Pauline Afonso (1, 2) , Martine Auclair (1, 2) , Franck Boccara (1, 3) , Marie-Christine Vantyghem (4) , Christine Katlama (5, 6) , Jacqueline Capeau (1, 2, 7) , Corinne Vigouroux (3, 1) , Martine Caron-Debarle (1, 2)

1 UMRS893 - Centre de Recherche Saint-Antoine
2 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
3 CHU Saint-Antoine [AP-HP]
4 Service d'Endocrinologie et Métabolisme
5 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
6 CHU Pitié-Salpêtrière [AP-HP]
7 CHU Tenon [AP-HP]

Background Some LMNA mutations responsible for lipodystrophies, and some HIV-protease inhibitors (PIs) induce accumulation of farnesylated prelamin A and premature senescence in some cell types. Patients with LMNA mutations or under PI-based therapy suffer from early atherosclerosis. The metalloprotease ZMPSTE24 is the key enzyme in prelamin A maturation. Aim We studied whether altered expression of ZMPSTE24 could contribute to vascular cell dysfunction in response to LMNA mutations or PI treatments. Methods Protein expression of prelamin A and ZMPSTE24 were evaluated in patients' cells and in human cultured VSMCs. Oxidative stress, inflammation, senescence and transdifferentiation/calcification were evaluated in VSMCs. Results Fibroblasts from LMNA-mutated lipodystrophic patients (mutations R482W, D47Y or R133L) and peripheral blood mononuclear cells from PI-treated-HIV-infected patients expressed increased prelamin A and decreased ZMPSTE24, which was also observed in VSMCs overexpressing mutant LMNA or treated with PIs. These alterations correlated with oxidative stress, inflammation, senescence and calcification (all p < 0.05). ZMPSTE24 silencing in native VSMCs recapitulated the mutant LMNA- and PI-induced accumulation of farnesylated prelamin A, oxidative stress, inflammation, senescence and calcification. A negative regulator of ZMPSTE24, miRNA-141-3p, was enhanced in LMNA-mutated or PI-treated VSMCs. The farnesylation inhibitors pravastatin and FTI-277, or the antioxidant N-acetyl cysteine, partly restored ZMPSTE24 expression, and concomitantly decreased oxidative stress, inflammation, senescence, and calcification of PI-treated VSCMs. Conclusions ZMPSTE24 downregulation is a major contributor in VSMC dysfunctions resulting from LMNA mutations or PI treatments that could translate in early atherosclerosis at the clinical level. These novel pathophysiological mechanisms could open new therapeutic perspectives for cardiovascular aging.

Mots clés: Vascular smooth muscle cells; ZMPSTE24; Prelamin A; Senescence; Osteogenic transdifferentiation; Atherosclerosis

Domaines: Médecine humaine et pathologie

Pauline Afonso, Martine Auclair, Franck Boccara, Marie-Christine Vantyghem, Christine Katlama, et al.. LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation. Atherosclerosis, 2016, 245, pp.200-211. ⟨10.1016/j.atherosclerosis.2015.12.012⟩. ⟨hal-01286022⟩