Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
复制标题
核结构和功能的缺陷会促进核纤层蛋白 A/C 缺陷小鼠的扩张型心肌病。
DOI：
10.1172/jci19448
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Fatkin,Dian
中科院分区：
文献类型：
--
作者：
Nikolova,Vesna;Leimena,Christiana;McMahon,AislingC;Tan,JuChiat;Chandar,Suchitra;Jogia,Dilesh;Kesteven,ScottH;Michalicek,Jan;Otway,Robyn;Verheyen,Fons;Rainer,Stephen;Stewart,ColinL;Martin,David;Feneley,MichaelP;Fatkin,Dian
Laminopathies are a group of disorders caused by mutations in theLMNAgene that encodes the nuclear lamina proteins, lamin A and lamin C; their pathophysiological basis is unknown. We report that lamin A/C–deficient (Lmna–/–) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction. IsolatedLmna–/–myocytes show reduced shortening with normal baseline and peak amplitude of Ca2+transients.Lmna–/–LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei. Electron microscopy ofLmna–/–cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network. Alterations in nuclear architecture are associated with defective nuclear function evidenced by decreased SREBP1 import, reduced PPARγ expression, and a lack of hypertrophic gene activation. These findings suggest a model in which the primary pathophysiological mechanism inLmna–/–mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension. Despite severe DCM, defects in nuclear function preventLmna–/–cardiomyocytes from developing compensatory hypertrophy and accelerate disease progression.
