Effects of Mechanical Stress and Carvedilol in Lamin A/C-Deficient Dilated Cardiomyopathy
Effects of Mechanical Stress and Carvedilol in Lamin A/C-Deficient Dilated Cardiomyopathy
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DOI：
10.1161/circresaha.109.204388
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发表时间：
2010-02-19
影响因子：
20.1
通讯作者：
Fatkin, Diane
中科院分区：
文献类型：
--
作者：
Chandar, Suchitra;Yeo, Li Sze;Fatkin, Diane
理论基础：LMNA基因的突变是家族性扩张型心肌病(DCM)的最常见原因，LMNA基因编码核层蛋白lamin A和lamin C。机械应激诱导的细胞凋亡被认为是层蛋白A/C缺陷心脏DCM的机制，但缺乏体内证据。目的：我们的目的是研究在杂合LmNA(+/-)基因敲除小鼠中改变机械应力的干预措施。方法和结果：在运动训练、胸主动脉缩窄和卡维地洛治疗前后评估心脏的结构和功能。LMNA(+/-)小鼠发展为成年型DCM，男性的疾病相对更严重。LMNA(+/-)心肌细胞核形态和核周结蛋白结构改变，对低渗应激反应增强，提示细胞骨架不稳定。尽管这些结构缺陷为机械应力诱导的损伤提供了模板，但接受6周中等或剧烈运动训练的LmNA(+/-)幼鼠没有表现出诱导细胞凋亡或加速DCM的现象。相比之下，有规律的适度运动可以抑制雄性LmNA(+/-)小鼠的DCM发展。胸主动脉收缩所产生的持续压力超负荷抑制了幼年野生型和Lmna(+/-)小鼠的心室收缩，在反应的时间-过程或严重程度上没有性别或基因差异。用β-受体阻滞剂卡维地洛治疗12-40周龄的雄性LmNA(+/-)小鼠，可以防止安慰剂治疗组小鼠的舒缩功能障碍。结论：这些数据表明，除了机械应激诱导的细胞凋亡外，其他因素也参与了DCM的发生，并首次证明定期适度运动和卡维地洛可以改善层蛋白A/C缺乏的心脏的疾病进展。(中国保监会决议2010；106：573-582。)
Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking.Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna(+/-)) mice.Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna(+/-) mice develop adult-onset DCM with relatively more severe disease in males. Lmna(+/-) cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna(+/-) mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna(+/-) mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna(+/-) mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna(+/-) mice from 12 to 40 weeks with the beta-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice.Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts. (Circ Res. 2010;106:573-582.)