Heart Institute, and Biology Department, SDSU Integrated Regenerative Research Institute, Life Sciences North, Room 426, 5500 Campanile Drive, San Diego, CA 92182, USA.
Basic Res Cardiol. 2013 Sep;108(5):375. doi: 10.1007/s00395-013-0375-8. Epub 2013 Aug 4.
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/EBPβ (Ccaat-enhanced binding protein β), 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.
心脏在壁面应力增加时发生病理性或生理性肥大的能力对于应对增加的工作量需求的长期代偿功能至关重要。虽然已经发表了大量关于涉及肥大的基本分子信号本质的信息，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。本研究的目的是描绘 Fn 在压力超负荷诱导的病理性心肌肥大和运动引起的生理性生长中的作用。成年期 Fn 的基因条件性缺失通过减弱激活 T 细胞活化核因子（NFAT）来抑制压力超负荷诱导的心肌细胞肥大。Fn 的缺失会延迟心力衰竭的发展并提高存活率。相比之下，Fn 的基因缺失对由自愿轮跑引起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）的下调对于诱导生理性生长程序至关重要，而 Fn 的缺失对其没有影响。Fn 与胎儿基因程序的上调以及体外心肌细胞肥大一起触发核 NFAT 易位。此外，体外胰岛素刺激诱导的生理性基因程序的激活被 Fn 减弱，而胰岛素对 Fn 诱导的病理性生长程序没有影响。Fn 通过 NFAT 激活促进体外和体内病理性心肌肥大。Fn 在体内对于生理性生长是可有可无的，并且 Fn 减弱了体外生理性生长程序的激活。
