Department of Gynecology, Obstetrics, and Reproductive Sciences, Center for Reproductive Sciences, University of California San Francisco, Box 0556, 513 Parnassus Avenue, San Francisco, CA 94143-0556, USA.
Basic Res Cardiol. 2011 Mar;106(2):249-62. doi: 10.1007/s00395-010-0138-8. Epub 2010 Dec 16.
PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation-contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has 'global' effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts.
PDE4 同工酶在控制啮齿动物心肌细胞中的 cAMP 信号中起着关键作用。PDE4 的缺失会影响兴奋-收缩偶联中的多个关键因素，并使小鼠易患心力衰竭。由于对人类心脏中的 PDE4 知之甚少，我们探讨了 PDE4 在啮齿动物和人类之间的心脏表达和功能在多大程度上是保守的。我们发现了相当多的相似之处，包括表达相当数量的 PDE4 活性、表达相同的 PDE4 亚型和剪接变体、将 PDE4 锚定到相同的亚细胞区室和大分子信号复合物，以及心力衰竭时 PDE4 活性和蛋白的下调。种间的主要区别在于人类心脏中非 PDE4 活性的含量比啮齿动物高五倍。因此，PDE4 失活在啮齿动物和人类中的作用不同。PDE4 抑制导致小鼠心肌细胞中几乎所有 PKA 底物的磷酸化增加，但在人类心肌细胞中仅增加了有限数量的蛋白质的磷酸化。我们的研究结果表明，PDE4 在啮齿动物和人类心脏中局部调节 cAMP 信号具有相似的作用。然而，PDE4 抑制对 cAMP 信号的“全局”影响仅在啮齿动物心脏中，因为 PDE4 在啮齿动物心脏中占总心脏 PDE 活性的很大一部分，但在人类心脏中则不然。这些差异可能解释了 PDE4 抑制在啮齿动物和人类心脏中的不同药理学效应。
