Critical role for FoxO3a-dependent regulation of p21CIP1/WAF1 in response to statin signaling in cardiac myocytes
Critical role for FoxO3a-dependent regulation of p21CIP1/WAF1 in response to statin signaling in cardiac myocytes
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DOI：
10.1161/01.res.0000254704.92532.b9
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发表时间：
2007-01-05
影响因子：
20.1
通讯作者：
von Harsdorf, Ruediger
中科院分区：
文献类型：
--
作者：
Hauck, Ludger;Harms, Christoph;von Harsdorf, Ruediger
他汀类药物是临床广泛使用的药物，对心肌肥大患者发挥有益的生长抑制作用。我们研究了细胞周期抑制剂p21（CIP 1/WAF 1）（p21）在他汀类药物依赖性抑制有丝分裂后心肌细胞肥大生长中的作用。我们证明洛伐他汀不能抑制p21（-/-）小鼠血管紧张素II引起的心肌肥厚，达特不能重建p21功能。p21蛋白转导可以在这些原本正常发育的动物中挽救他汀类药物的作用。洛伐他汀特异性招募叉头框FoxO 3a转录因子到p21启动子，介导p21基因的转录反式激活，如在分离的原代心肌细胞中分析的。洛伐他汀还刺激蛋白激酶B/Akt激酶活性，并且Akt依赖性磷酸化迫使p21在细胞质中，在细胞质中它抑制有助于抑制心肌细胞肥大的Rho激酶。RNA干扰导致p21或FoxO 3a的缺失导致洛伐他汀信号转导的普遍抑制。这些结果表明，p21作为FoxO 3a下游靶点介导他汀衍生的抗肥大反应。总之，我们的遗传和生化数据描绘了一个重要的功能，p21的他汀类药物依赖性抑制心肌细胞肥大。
Statins are widely used clinical drugs that exert beneficial growth-suppressive effects in patients with cardiac hypertrophy. We investigated the role of the cell cycle inhibitor p21(CIP1/WAF1) (p21) in statin-dependent inhibition of hypertrophic growth in postmitotic cardiomyocytes. We demonstrate that lovastatin fails to inhibit cardiac hypertrophy to angiotensin II in p21(-/-) mice and that reconstitution of p21 function by TAT. p21 protein transduction can rescue statin action in these otherwise normally developed animals. Lovastatin specifically recruits the forkhead box FoxO3a transcription factor to the p21 promoter, mediating transcriptional transactivation of the p21 gene as analyzed in isolated primary cardiomyocytes. Lovastatin also stimulates protein kinase B/Akt kinase activity, and Akt-dependent phosphorylation forces p21 in the cytoplasm, where it inhibits Rho-kinases contributing to the suppression of cardiomyocyte hypertrophy. Loss of p21 or FoxO3a by RNA interference causes a general inhibition of lovastatin signal transduction. These results suggest that p21 functions as FoxO3a downstream target to mediate an statin-derived anti-hypertrophic response. Taken together, our genetic and biochemical data delineate an essential function of p21 for statin-dependent inhibition of cardiac myocyte hypertrophy.