Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

被引：66

作者：

Bidault, Guillaume ^{[1
,2
,7
]}

Garcia, Marie ^{[1
,2
,7
]}

Vantyghem, Marie-Christine ^{[3
]}

Ducluzeau, Pierre-Henri ^{[4
]}

Morichon, Romain ^{[5
]}

Thiyagarajah, Kayathri ^{[1
,2
,7
]}

Moritz, Sylviane ^{[2
,7
]}

Capeau, Jacqueline ^{[1
,2
,6
,7
]}

Vigouroux, Corinne ^{[1
,2
,6
,7
]}

Bereziat, Veronique ^{[1
,2
,7
]}

机构：

[1] UPMC Univ Paris 06, UMR S938, Paris, France

[2] Fac Med Pierre & Marie Curie, Ctr Rech St Antoine, INSERM, UMR S938, Paris, France

[3] CHRU Lille, Serv Endocrinol & Malad Metab, INSERM, U859, F-59037 Lille, France

[4] Hosp Civils, Ctr Rech Nutr Humaine, Lyon, France

[5] Inst Federatif Rech Sante St Antoine IFR 65, Paris, France

[6] Hop Tenon, AP HP, Serv Biochim & Hormonol, F-75970 Paris, France

[7] Inst Cardiometab & Nutr, ICAN, Paris, France

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2013年 / 33卷 / 09期

关键词：

arteriosclerosis; endothelial cells; laminin A/C; oxidative stress; prelamin A; statins; HMG-CoA; HUTCHINSON-GILFORD-PROGERIA; FAMILIAL PARTIAL LIPODYSTROPHY; CORONARY-HEART-DISEASE; A/C R482Q MUTATION; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; MOUSE MODEL; DNA-DAMAGE; LAMIN A/C; FARNESYLTRANSFERASE INHIBITOR;

D O I：

10.1161/ATVBAHA.113.301933

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2162 / 2171

页数：10

共 48 条

[1] Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy [J].

Cao, H ;

Hegele, RA .

HUMAN MOLECULAR GENETICS, 2000, 9 (01) :109-112

[2] Altered pre-lamin A processing is a common mechanism leading to lipodystrophy [J].

Capanni, C ;

Mattioli, E ;

Columbaro, M ;

Lucarelli, E ;

Parnaik, VK ;

Novelli, G ;

Wehnert, M ;

Cenni, V ;

Maraldi, NM ;

Squarzoni, S ;

Lattanzi, G .

HUMAN MOLECULAR GENETICS, 2005, 14 (11) :1489-1502

[3] Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome [J].

Capell, BC ;

Erdos, MR ;

Madigan, JP ;

Fiordalisi, JJ ;

Varga, R ;

Conneely, KN ;

Gordon, LB ;

Der, CJ ;

Cox, AD ;

Collins, FS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (36) :12879-12884

[4] A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model [J].

Capell, Brian C. ;

Olive, Michelle ;

Erdos, Michael R. ;

Cao, Kan ;

Faddah, Dina A. ;

Tavarez, Urraca L. ;

Conneely, Karen N. ;

Qu, Xuan ;

San, Hong ;

Ganesh, Santhi K. ;

Chen, Xiaoyan ;

Avallone, Hedwig ;

Kolodgie, Frank D. ;

Virmani, Renu ;

Nabel, Elizabeth G. ;

Collins, Francis S. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (41) :15902-15907

[5] Mechanisms of cardiovascular disease in accelerated aging syndromes [J].

Capell, Brian C. ;

Collins, Francis S. ;

Nabel, Elizabeth G. .

CIRCULATION RESEARCH, 2007, 101 (01) :13-26

[6] Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence [J].

Caron, M. ;

Auclair, M. ;

Donadille, B. ;

Bereziat, V. ;

Guerci, B. ;

Laville, M. ;

Narbonne, H. ;

Bodemer, C. ;

Lascols, O. ;

Capeau, J. ;

Vigouroux, C. .

CELL DEATH AND DIFFERENTIATION, 2007, 14 (10) :1759-1767

[7] Genomic instability in mice lacking histone H2AX [J].

Celeste, A ;

Petersen, S ;

Romanienko, PJ ;

Fernandez-Capetillo, O ;

Chen, HT ;

Sedelnikova, OA ;

Reina-San-Martin, B ;

Coppola, V ;

Meffre, E ;

Difilippantonio, MJ ;

Redon, C ;

Pilch, DR ;

Olaru, A ;

Eckhaus, M ;

Camerini-Otero, RD ;

Tessarollo, L ;

Livak, F ;

Manova, K ;

Bonner, WM ;

Nussenzweig, MC ;

Nussenzweig, A .

SCIENCE, 2002, 296 (5569) :922-927

[8] HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells [J].

Coffinier, Catherine ;

Hudon, Sarah E. ;

Farber, Emily A. ;

Chang, Sandy Y. ;

Hrycyna, Christine A. ;

Young, Stephen G. ;

Fong, Loren G. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (33) :13432-13437

[9] Nuclear shape, mechanics, and mechanotransduction [J].

Dahl, Kris Noel ;

Ribeiro, Alexandre J. S. ;

Lammerding, Jan .

CIRCULATION RESEARCH, 2008, 102 (11) :1307-1318

[10] Role of endothelial dysfunction in atherosclerosis [J].

Davignon, J ;

Ganz, P .

CIRCULATION, 2004, 109 (23) :27-32

← 1 2 3 4 5 →