The emperor's new clothes: PDE5 and the heart.
The emperor's new clothes: PDE5 and the heart.
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DOI：
10.1371/journal.pone.0118664
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Brozovich FV
中科院分区：
文献类型：
--
作者：
Degen CV;Bishu K;Zakeri R;Ogut O;Redfield MM;Brozovich FV
磷酸二酯酶-5（PDE 5）在肺血管中高度表达，但其在心肌中的表达存在争议。环磷酸鸟苷（cGMP）激活蛋白激酶G（PKG），这已被假设为钝化心脏肥大和心力衰竭的负性重塑。尽管已表明PDE 5在心肌细胞中cGMP的分解中起重要作用，因此在心肌中PKG调节中起重要作用，但RELAX试验测试了PDE 5抑制对射血分数保留的心力衰竭（HFpEF）患者运动能力的影响，未能显示有益效果。这些结果突出了关于PDE 5在健康和衰竭心脏中的作用和表达的争议。本研究使用一维和二维电泳和蛋白质印迹法检测小鼠（经主动脉缩窄前后）、犬（对照和HFpEF）以及人（健康和衰竭）心脏中的PDE 5表达。我们无法在任何心脏组织裂解物中检测到PDE 5，而PDE 5存在于用作阳性对照的鼠和牛肺样品中。这些结果表明，如果PDE 5在心脏组织中表达，则其以非常低的量存在，因为在所检查的人类或任何心力衰竭模型中均未检测到PDE 5。因此，在心肌中，PDE 5不太可能参与cGMP-PKG信号传导的调节，因此PDE 5不代表用于治疗心脏肥大的合适药物靶标。这些结果强调了在临床试验设计之前进行严格调查的重要性。
Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.
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影响因子：
3.7
作者：
Mohammed, Selma F.;Storlie, Jimmy R.;Oehler, Elise A.;Bowen, Lorna A.;Korinek, Josef;Lam, Carolyn S. P.;Simari, Robert D.;Burnett, John C., Jr.;Redfield, Margaret M.
通讯作者：
Redfield, Margaret M.
DOI：
10.1016/j.bbrc.2005.06.183
发表时间：
2005-09-02
影响因子：
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通讯作者：
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影响因子：
120.7
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影响因子：
24
作者：
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通讯作者：
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影响因子：
9.7
作者：
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通讯作者：
Guazzi, Maurizio D.