A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure
A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure
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DOI：
10.1073/pnas.0608791103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
van Rooij, Eva;Sutherland, Lillian B.;Olson, Eric N.
不同形式的损伤和应激引起成人心肌细胞的肥大生长反应，其特征是细胞大小增加，蛋白质合成增强，肌节组装，胎儿基因重新激活，通常最终导致心力衰竭和猝死。鉴于microRNAs(MiRNAs)在细胞表型调控中的作用，我们寻找在心肌肥厚和心力衰竭过程中受到调控的miRNAs。我们描述了>；12miRNAs在小鼠心脏组织中上调或下调，以响应横动脉收缩或激活的钙调神经磷酸酶的表达，这些刺激诱导了病理性心脏重构。其中许多miRNAs在衰竭的人类心脏中也受到类似的调控。强迫过表达应激诱导的miRNAs足以诱导培养的心肌细胞肥大。同样，在心肌肥大期间上调的miR-195心脏过度表达，导致转基因小鼠心脏病理性生长和心力衰竭。这些发现揭示了特定的miRNAs在控制心脏肥大生长和心腔重构中的重要作用，以响应病理信号，并指出miRNAs是心脏病的潜在治疗靶点。
Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe > 12 miRNAs that are up- or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease.