Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth
Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth
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DOI：
10.1007/s00395-013-0375-8
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发表时间：
2013-09-01
影响因子：
9.5
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
--
作者：
Konstandin, Mathias H.;Voelkers, Mirko;Sussman, Mark A.
心脏在壁应力增加时发生病理性或生理性肥大的能力，对于响应增加的工作负荷需求的长期代偿功能至关重要。虽然已经发表了大量关于肥厚相关的基本分子信号的性质的信息，但细胞外基质蛋白纤维连接蛋白(FN)在肥大信号中的作用尚不清楚。本研究的目的是阐明纤维连接蛋白在压力超负荷引起的病理性心肌肥大和运动促进的生理性生长中的作用。成年期遗传性条件消融FN可通过减弱活化T细胞核因子(NFAT)的激活来钝化压力超负荷所致的心肌细胞肥大。FN的丢失延缓了心力衰竭的发展，提高了存活率。相反，FN的基因缺失对自愿车轮运动诱导的生理性心脏生长没有影响。转录因子c/EBPβ(Ccaat增强结合蛋白β)的下调是诱导生理生长程序所必需的，但不受Fn缺失的影响。核NFAT易位是由FN与胎儿基因程序的上调和体外培养的心肌细胞肥大共同触发的。此外，体外胰岛素刺激诱导的生理基因程序的激活可被FN减弱，而胰岛素对FN诱导的病理生长程序没有影响。FN通过激活NFAT在体外和体内参与病理性心肌细胞肥大。在体内，Fn对于生理生长是必不可少的，而在体外，Fn减弱了生理生长程序的激活。
Ability of the heart to undergo pathological or physiological hypertrophy upon increased wall stress is critical for long-term compensatory function in response to increased workload demand. While substantial information has been published on the nature of the fundamental molecular signaling involved in hypertrophy, the role of extracellular matrix protein Fibronectin (Fn) in hypertrophic signaling is unclear. The objective of the study was to delineate the role of Fn during pressure overload-induced pathological cardiac hypertrophy and physiological growth prompted by exercise. Genetic conditional ablation of Fn in adulthood blunts cardiomyocyte hypertrophy upon pressure overload via attenuated activation of nuclear factor of activated T cells (NFAT). Loss of Fn delays development of heart failure and improves survival. In contrast, genetic deletion of Fn has no impact on physiological cardiac growth induced by voluntary wheel running. Down-regulation of the transcription factor c/EBP beta (Ccaat-enhanced binding protein beta), which is essential for induction of the physiological growth program, is unaffected by Fn deletion. Nuclear NFAT translocation is triggered by Fn in conjunction with up-regulation of the fetal gene program and hypertrophy of cardiomyocytes in vitro. Furthermore, activation of the physiological gene program induced by insulin stimulation in vitro is attenuated by Fn, whereas insulin had no impact on Fn-induced pathological growth program. Fn contributes to pathological cardiomyocyte hypertrophy in vitro and in vivo via NFAT activation. Fn is dispensable for physiological growth in vivo, and Fn attenuates the activation of the physiological growth program in vitro.