Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition
Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition
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DOI：
10.1016/j.yjmcc.2008.12.008
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发表时间：
2009-04-01
影响因子：
5
通讯作者：
Kass, David A.
中科院分区：
文献类型：
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作者：
Nagayama, Takahiro;Hsu, Steven;Kass, David A.
通过增强环化酶活性或通过磷酸二酯酶5型（PDE 5A）阻碍cGMP水解实现的心肌cGMR增加，抑制细胞和整个器官肥大。后者的功效还需要环化酶刺激，并且可能取决于可由cGMP刺激的激酶（cGK-1）抑制的适应不良信号传导的共激活。因此，PDE 5A抑制剂可能矛盾地对较高的压力过载应力比较低的压力过载应力更有效。为了测试这一点，使小鼠经受重度或中度经主动脉收缩（sTAC，mTAC）6周+/-与口服西地那非（SIL 200 mg/kg/d）共同治疗。3周后，左心室质量（LVM）增加了130%，sTAC和SIL使其减弱了50%。使用mTAC时，3周时左心室质量增加56%，但不受SIL影响，而6周后左心室质量增加90%被SIL抑制，SIL轻微改变左心室功能和重塑，直到刺激更多肥大和重塑的后期阶段。SIL刺激cGK-1活性在3周和6周的mTAC相似。然而，病理性应激信号与sTAC或晚期mTAC不同的是，在3周mTAC后，细胞外基质（例如钙调神经磷酸酶、ERK-MAP激酶）几乎没有激活，而sTAC或晚期mTAC的活性增加，SIL对其进行抑制。（3周mTAQ、GSK 3 β和Akt磷酸化没有改变，但SIL增强了其磷酸化。然而，随着更严重的肥大（6周mTAC和3周sTAC），两种激酶都高度磷酸化，SIL处理降低了磷酸化。因此，PDE 5A抑制剂在高于较低幅度的应激下更有效地对抗心脏压力超负荷应激重塑，与cGK-1刺激靶向的病理信号传导激活偶联。这种调节可能会影响不同疾病模型对PDE 5A抑制剂的反应。(C)2009 Elsevier Inc. All rights reserved.
Increased myocardial cGMR achieved by enhancing cyclase activity or impeding cGMP hydrolysis by phosphodiesterase type-5 (PDE5A), suppresses cellular and whole organ hypertrophy. The efficacy of the latter also requires cyclase stimulation and may depend upon co-activation of maladaptive signaling suppressible by cGMP-stimulated kinase (cGK-1). Thus, PDE5A inhibitors could paradoxically be more effective against higher than lower magnitudes of pressure-overload stress. To test this, mice were subjected to severe or moderate trans-aortic constriction (sTAC, mTAC) for 6 wks +/- co-treatment with oral sildenafil (SIL 200 mg/kg/d). LV mass (LVM) rose 130% after 3-wks sTAC and SIL blunted this by 50%. With mTAC, LVM rose 56% at 3 wks but was unaffected by SIL, whereas a 90% increase in LVM after 6 wks was suppressed by SIL SIL minimally altered LV function and remodeling with mTAC until later stages that stimulated more hypertrophy and remodeling. SIL stimulated cGK-1 activity similarly at 3 and 6 wks of mTAC. However, pathologic stress signaling (e.g. calcineurin, ERK-MAPkinase) was little activated after 3-wk mTAC, unlike sTAC or later stage mTAC when activity increased and SIL suppressed it. With modest hypertrophy (3-wk mTAQ, GSK3 beta and Akt phosphorylation were unaltered but SIL enhanced it. However, with more severe hypertrophy (6-wk mTAC and 3-wk sTAC), both kinases were highly phosphorylated and SIL treatment reduced it. Thus, PDE5A-inhibition counters cardiac pressure-overload stress remodeling more effectively at higher than lower magnitude stress, coupled to pathologic signaling activation targetable by cGK-1 stimulation. Such regulation could impact responses of varying disease models to PDE5A inhibitors. (C) 2009 Elsevier Inc. All rights reserved.