PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways.
PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways.
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DOI：
10.1152/ajpheart.00852.2013
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发表时间：
2014-04
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通讯作者：
C. Vettel;Simon Lämmle;S. Ewens;C. Cervirgen;Julius Emons;Anita Ongherth;M. Dewenter;D. Lindner;D. Westermann;V. O. Nikolaev;Susanne Lutz;Wolfram-Hubertus Zimmermann;A. El-Armouche
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作者：
C. Vettel;Simon Lämmle;S. Ewens;C. Cervirgen;Julius Emons;Anita Ongherth;M. Dewenter;D. Lindner;D. Westermann;V. O. Nikolaev;Susanne Lutz;Wolfram-Hubertus Zimmermann;A. El-Armouche
最近的研究表明，信号分子cAMP和cGMP通过负调节与成纤维细胞向肌成纤维细胞（MyoCF）转化相关的途径而具有抗纤维化作用。磷酸二酯酶2（PDE 2）具有受环鸟苷酸刺激的独特性质，这会导致环鸟苷酸水解显着增加，从而介导两种途径之间的负串扰。PDE 2最近在心肌细胞中进行了研究;在这里，我们特别讨论了其在成纤维细胞转化和心脏纤维化中的作用。PDE 2在新生大鼠心脏成纤维细胞（CF）和心肌细胞中大量表达。CF中PDE 2的过度表达强烈降低了基础和异丙肾上腺素诱导的cAMP合成，即使在没有外源性促纤维化刺激的情况下，这种降低也足以诱导MyoCF转化。成纤维细胞衍生的工程化结缔组织（ECT）的功能性应力-应变实验表明，过表达PDE 2的ECT具有更高的刚度。在cGMP方面，无论是基础还是心房利钠肽诱导的cGMP水平均不受PDE 2的影响，而对一氧化氮供体硝普钠的反应略有但显著降低。有趣的是，尽管持续降低cAMP水平，但两种cGMP升高刺激都能够完全阻止PDE 2诱导的MyoCF表型，这是一种双轨机制。总之，PDE 2加速CF向MyoCF的转化，导致ECT的刚度更大。心房利钠肽和硝普钠介导的cGMP合成完全逆转PDE 2诱导的成纤维细胞转化。因此，PDE 2可以增强心脏重塑，但这种作用也可以通过增强cGMP来克服。cAMP和cGMP作为抗纤维化调节剂的冗余作用可被视为心力衰竭的保护机制。
Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.