Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy
Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy
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DOI：
10.1073/pnas.97.3.1196
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发表时间：
2000-02-01
影响因子：
11.1
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Taigen, T;De Windt, LJ;Molkentin, JD
心脏肥大是未来发病率和死亡率的主要预测因素。最近的研究集中在确定调节心肌细胞反应性的分子信号通路，目的是调节病理性肥大程序。心肌细胞肥大的一个潜在调节因子是钙敏感性磷酸酶钙调神经磷酸酶。我们在这里表明，钙调神经磷酸酶的酶活性，mRNA和蛋白质水平增加培养的新生大鼠心肌细胞肥大激动剂，如血管紧张素II，苯肾上腺素，和1%胎牛血清。这种钙调磷酸酶活性的诱导与钙调磷酸酶A β（CnA β）mRNA和蛋白质的增加有关，但与CnA α或CnA γ无关。用表达钙调磷酸酶的非竞争性肽抑制剂（称为cain）的腺病毒特异性抑制钙调磷酸酶酶活性的激动剂依赖性增加[Lai，M. M.，伯内特，体育，Wolosker，H.，Blackshaw，S，& Snyder，5. H.（'1998）J. Biol，Chem，273，18325-18331]。用cain或仅表达AKAP 79的钙调神经磷酸酶抑制结构域的腺病毒靶向抑制钙调神经磷酸酶，响应于血管紧张素II、苯丙氨酸，减弱心肌细胞肥大和心房利钠因子表达。和1%胎牛血清。这些数据表明，钙调神经磷酸酶是一个重要的调节心肌细胞肥大的某些激动剂的反应，并表明，环孢素A和FK 506的功能，以减轻心脏肥大特异性抑制钙调神经磷酸酶。
Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin activity was associated with an increase in calcineurin A beta (CnA beta) mRNA and protein, but not in CnA alpha or CnA gamma. Agonist-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S, & Snyder, 5. H. ('1998) J. Biol, Chem, 273, 18325-18331]. Targeted inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine. and 1% fetal bovine serum. These data demonstrate that calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting calcineurin.