{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:22:16Z","timestamp":1791332536924,"version":"4.3.1"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>\n              Some mutations in\n              <jats:italic>LMNA<\/jats:italic>\n              , 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\n              <jats:italic>LMNA<\/jats:italic>\n              mutations could have a direct role on the vascular wall cells.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              We analyzed the cardiovascular phenotype of 19 FPLD2 patients aged &gt;30 years with\n              <jats:italic>LMNA<\/jats:italic>\n              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\u2019 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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              <jats:italic>LMNA<\/jats:italic>\n              p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients\u2019 early atherosclerosis.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.113.301933","type":"journal-article","created":{"date-parts":[[2013,7,12]],"date-time":"2013-07-12T05:39:07Z","timestamp":1373607547000},"page":"2162-2171","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":91,"title":["Lipodystrophy-Linked\n            <i>LMNA<\/i>\n            p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction"],"prefix":"10.1161","volume":"33","author":[{"given":"Guillaume","family":"Bidault","sequence":"first","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Garcia","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Vantyghem","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Henri","family":"Ducluzeau","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Morichon","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayathri","family":"Thiyagarajah","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylviane","family":"Moritz","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Capeau","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Vigouroux","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"B\u00e9r\u00e9ziat","sequence":"additional","affiliation":[{"name":"From the UPMC Univ Paris 06, UMR_S938, Paris, France (G.B., M.G., K.T., J.C., C.V., V.B.); INSERM UMR_S938, Centre de Recherche Saint-Antoine, Facult\u00e9 de M\u00e9decine Pierre et Marie Curie, Site Saint-Antoine, Paris, France (G.B., M.G., K.T., S.M., J.C., C.V., V.B.); Service d\u2019Endocrinologie et Maladies M\u00e9taboliques, INSERM U 859, Centre Hospitalier R\u00e9gional et Universitaire (CHRU) de Lille, Lille, France (M.-C.V.); Centre de Recherche en Nutrition Humaine, Hospices Civils, Lyon, France (P.-H.D.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000547"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2999"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.1.109"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/72807"},{"key":"e_1_3_4_6_2","first-page":"170","article-title":"Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety).","volume":"84","author":"Garg A","year":"1999","unstructured":"Garg A, Peshock RM, Fleckenstein JL. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 1999;84:170\u2013174.","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.11.1958"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.10.5.652"},{"key":"e_1_3_4_9_2","first-page":"1776","article-title":"Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety).","volume":"85","author":"Garg A","year":"2000","unstructured":"Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 2000;85:1776\u20131782.","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.18.2225"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706898"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.110.209460"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2004.10.064"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi158"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402197"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1084125"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01629"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511133103"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600012103"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.153692"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03263"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1266"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.109.902056"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr327"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506001102"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124875"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807840105"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1786"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202529109"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000013836.85741.17"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000131515.03336.f8"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000188210.72062.10"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000150649.39934.13"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.110.213603"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3642"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3109\/10715762.2012.663913"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.11.012"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069398"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.34"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.96.12.4219"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.15.1767"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(03)00280-6"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107477"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010874"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.25.2494"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000026393.47805.21"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.108.182899"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0704212104"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.108.173989"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.113.301933","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:18:48Z","timestamp":1715555928000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.113.301933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9]]},"references-count":48,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2013,9]]}},"alternative-id":["10.1161\/ATVBAHA.113.301933"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.113.301933","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9]]},"assertion":[{"value":"2013-01-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-06-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-07-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}