Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway
Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway
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DOI：
10.1093/cvr/cvn324
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发表时间：
2009-02-01
影响因子：
10.8
通讯作者：
Takimoto, Eiki
中科院分区：
文献类型：
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作者：
Hsu, Steven;Nagayama, Takahiro;Takimoto, Eiki
西地那非（SIL）对环鸟苷酸（cGMP）特异性磷酸二酯酶5（PDE 5）的抑制作用可激活心肌cGMP依赖性蛋白激酶G（PKG）并减弱心肌肥大。迄今为止，心肌中PKG的唯一记录的靶点是丝氨酸-苏氨酸磷酸酶钙调神经磷酸酶（Cn），其是病理性心脏肥大的核心。我们测试了Cn抑制是否是观察SIL的抗肥大作用所必需的。缺乏Cn-A β亚基（CnA β（-/-））的小鼠和野生型（WT）对照在有或没有SIL（200 mg/kg/天，p.o.）三个星期。在WT中，TAC诱导的Cn表达和活性升高在CnA β（-/-）心脏中不存在，并且后者相应地发生较少的心脏肥大（心脏重量/胫骨长度增加50% vs. 100%，P < 0.03）和室扩张。SIL在CnA β（-/-）小鼠中仍然有效，与WT相似地增加PKG活性，抑制肥大和胎儿基因表达，并在不改变后负荷的情况下增强心脏功能。TAC刺激的钙-钙调蛋白激酶II，Akt和糖原合成酶激酶3 β在两组中（在CnA β（-/-）心脏中首次升高更多），SIL也类似地抑制这些。在WT-TAC而不是CnA β（-/-）心脏中观察到的细胞外信号调节激酶的激活也被SIL. PDE 5A抑制及其伴随的PKG激活抑制，即使没有Cn激活，也能抑制肥大并改善心脏功能。这是通过其对几种替代途径的调节而发生的，这些途径可能是由伴随的远端靶向或对共同的近端淋巴结的活性引起的。
Cyclic GMP (cGMP)-specific phosphodiesterase 5 (PDE5) inhibition by sildenafil (SIL) activates myocardial cGMP-dependent protein kinase G (PKG) and blunts cardiac hypertrophy. To date, the only documented target of PKG in myocardium is the serine-threonine phosphatase calcineurin (Cn), which is central to pathological cardiac hypertrophy. We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL.Mice lacking the Cn-A beta subunit (CnA beta(-/-)) and wild-type (WT) controls were subjected to transverse aorta constriction (TAC) with or without SIL (200 mg/kg/day, p.o.) for 3 weeks. TAC-induced elevation of Cn expression and activity in WT was absent in CnA beta(-/-) hearts, and the latter accordingly developed less cardiac hypertrophy (50 vs. 100% increase in heart weight/tibia length, P < 0.03) and chamber dilation. SIL remained effective in CnA beta(-/-) mice, increasing PKG activity similarly as in WT, suppressing hypertrophy and fetal gene expression, and enhancing heart function without altering afterload. TAC-stimulated calcium-calmodulin kinase II, Akt, and glycogen synthase kinase 3 beta in both groups (the first rising more in CnA beta(-/-) hearts), and SIL also suppressed these similarly. Activation of extracellular signal-regulated kinase observed in WT-TAC but not CnA beta(-/-) hearts was also suppressed by SIL.PDE5A inhibition and its accompanying PKG activation blunt hypertrophy and improve heart function even without Cn activation. This occurs by its modulation of several alternative pathways which may result from concomitant distal targeting, or activity against a common proximal node.