Afilalo Jonathan, Sebag Igal A, Chalifour Lorraine E, Rivas Daniel, Akter Rahima, Sharma Kamal, Duque Gustavo
Division of Internal Medicine, Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1451-6. doi: 10.1152/ajpheart.01194.2006. Epub 2007 May 18.
Lamin A and C (A/C) are type V intermediate filaments that form the nuclear lamina. Lamin A/C mutations lead to reduced expression of lamin A/C and diverse phenotypes such as familial cardiomyopathies and accelerated aging syndromes. Normal aging is associated with reduced expression of lamin A/C in osteoblasts and dermal fibroblasts but has never been assessed in cardiomyocytes. Our objective was to compare the expression of lamin A/C in cardiomyocytes of old (24 mo) versus young (4 mo) C57Bl/6J mice using a well-validated mouse model of aging. Lamin B1 was used as a control. Immunohistochemical and immunofluorescence analyses showed reduced expression of lamin A/C in cardiomyocyte nuclei of old mice (proportion of nuclei expressing lamin A/C, 9% vs. 62%, P < 0.001). Lamin A/C distribution was scattered peripherally and perinuclear in old mice, whereas it was homogeneous throughout the nuclei in young mice. Western blot analyses confirmed reduced expression of lamin A/C in nuclear extracts of old mice (ratio of lamin A/C to B1, 0.6 vs. 1.2, P < 0.01). Echocardiographic studies showed increased left ventricular wall thickness with preserved cavity size (concentric remodeling), increased left ventricular mass, and a slight reduction in fractional shortening in old mice. This is the first study to show that normal aging is associated with reduced expression and altered distribution of lamin A/C in nuclei of cardiomyocytes.
核纤层蛋白A和C（A/C）是形成核纤层的V型中间丝。核纤层蛋白A/C突变会导致其表达减少，并引发多种表型，如家族性心肌病和加速衰老综合征。正常衰老与成骨细胞和真皮成纤维细胞中核纤层蛋白A/C的表达减少有关，但从未在心肌细胞中进行过评估。我们的目的是使用经过充分验证的衰老小鼠模型，比较老年（24个月）和年轻（4个月）C57Bl/6J小鼠心肌细胞中核纤层蛋白A/C的表达。核纤层蛋白B1用作对照。免疫组织化学和免疫荧光分析显示，老年小鼠心肌细胞核中核纤层蛋白A/C的表达减少（表达核纤层蛋白A/C的细胞核比例，9%对62%，P<0.001）。在老年小鼠中，核纤层蛋白A/C分布在外周和核周呈散在分布，而在年轻小鼠中，其在整个细胞核中分布均匀。蛋白质印迹分析证实老年小鼠核提取物中核纤层蛋白A/C的表达减少（核纤层蛋白A/C与B1的比值，0.6对1.2，P<0.01）。超声心动图研究显示，老年小鼠左心室壁厚度增加，腔径保持不变（向心性重塑），左心室质量增加，缩短分数略有降低。这是第一项表明正常衰老与心肌细胞核中核纤层蛋白A/C表达减少和分布改变相关的研究。
