Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice
Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice
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DOI：
10.1161/circresaha.107.160978
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发表时间：
2007-12-07
影响因子：
20.1
通讯作者：
Franchini, Kleber G.
中科院分区：
文献类型：
--
作者：
Clemente, Carolina F. M. Z.;Tornatore, Thais F.;Franchini, Kleber G.
肥厚是慢性超负荷心脏衰竭发生的关键事件。粘着斑激酶（FAK）作为增加负荷诱导的肥大的介导剂引起了特别的关注。在这里，我们证明了增加的表达和磷酸化的FAK在肥大的左心室（LV）的带状疱疹小鼠。我们使用RNA干扰策略来研究FAK信号传导是否在负荷诱导的LV肥大和衰竭的病理生理学中起作用。在正常和肥大的LV中，经颈静脉递送特异性小干扰RNA诱导了长时间的FAK沉默（约70%）。心肌FAK沉默伴随着预防，以及逆转，负荷诱导的左心室肥大。尽管持续的压力超负荷，但用靶向FAK的小干扰RNA治疗的束缚小鼠的LV功能得到保留，存活率较高。在从LV收获的心肌细胞和成纤维细胞中的研究证实了全身施用的特异性小干扰RNA沉默两种细胞类型中的FAK的能力。进一步的分析表明，心肌细胞肥大性生长的衰减和β-肌球蛋白重链的表达在超载LV的上升。此外，FAK沉默被证明可以减弱过载LV中纤维化、胶原含量和基质金属蛋白酶-2活性的上升，以及从过载LV中收获的成纤维细胞中基质金属蛋白酶-2蛋白表达的上升。这项研究提供了新的证据表明，FAK可能参与了多个方面的病理生理学的心肌肥厚和压力超负荷引起的衰竭。
Hypertrophy is a critical event in the onset of failure in chronically overloaded hearts. Focal adhesion kinase (FAK) has attracted particular attention as a mediator of hypertrophy induced by increased load. Here, we demonstrate increased expression and phosphorylation of FAK in the hypertrophic left ventricles (LVs) of aortic-banded mice. We used an RNA interference strategy to examine whether FAK signaling plays a role in the pathophysiology of load-induced LV hypertrophy and failure. Intrajugular delivery of specific small interfering RNA induced prolonged FAK silencing (approximate to 70%) in both normal and hypertrophic LVs. Myocardial FAK silencing was accompanied by prevention, as well as reversal, of load-induced left ventricular hypertrophy. The function of LVs was preserved and the survival rate was higher in banded mice treated with small interfering RNA targeted to FAK, despite the persistent pressure overload. Studies in cardiac myocytes and fibroblasts harvested from LVs confirmed the ability of the systemically administered specific small interfering RNA to silence FAK in both cell types. Further analysis indicated attenuation of cardiac myocyte hypertrophic growth and of the rise in the expression of beta-myosin heavy chain in overloaded LVs. Moreover, FAK silencing was demonstrated to attenuate the rise in the fibrosis, collagen content, and activity of matrix metalloproteinase-2 in overloaded LVs, as well as the rise of matrix metalloproteinase-2 protein expression in fibroblasts harvested from overloaded LVs. This study provides novel evidence that FAK may be involved in multiple aspects of the pathophysiology of cardiac hypertrophy and failure induced by pressure overload.