CNRS UMR 7213, Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
PLoS One. 2010 Dec 3;5(12):e14227. doi: 10.1371/journal.pone.0014227.
Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored.Rats developed arterial hypertension associated with a slight cardiac hypertrophy (+24%). cAMP-PDE4 activity was specifically increased while cGMP-PDE activities were broadly increased (+130% for PDE1; +76% for PDE2; +113% for PDE5) and associated with increased expressions for PDE1A, PDE1C and PDE5A. The cGMP-PDE1 activation by Ca(2+)/CaM was reduced. BNP expression was increased by 3.5-fold, while NOX2 expression was reduced by 66% and AMP kinase activation was increased by 64%. In early cardiac hypertrophy induced by angiotensin II, all specific PDE activities in left cardiac ventricles were increased, favoring an increase in cGMP hydrolysis by PDE1, PDE2 and PDE5. Increased cAMP hydrolysis was related to PDE4. We observed the establishment of two cardioprotective mechanisms and we suggest that these mechanisms could lead to increase intracellular cGMP: i) increased expression of BNP could increase "particulate" cGMP pool; ii) increased activation of AMPK, subsequent to increase in PDE4 activity and 5'AMP generation, could elevate "soluble" cGMP pool by enhancing NO bioavailability through NOX2 down-regulation. More studies are needed to support these assumptions. Nevertheless, our results suggest a potential link between PDE4 and AMPK/NOX2 and they point out that cGMP-PDEs, especially PDE1 and PDE2, may be interesting therapeutic targets in preventing cardiac hypertrophy.
左心室肥厚导致心力衰竭，代表着导致过早死亡的高风险。环核苷酸（cAMP 和 cGMP）在心脏收缩中起主要作用，环核苷酸磷酸二酯酶（PDEs）参与了各种晚期心脏疾病的不同阶段。我们研究了它们在左心室肥厚发展的最初阶段的贡献。雄性 Wistar 大鼠通过使用渗透微型泵进行两周的慢性血管紧张素 II 输注进行治疗。左心室用作分析的总匀浆。研究了 PDE1 至 PDE5 的特异性活性以及蛋白和 mRNA 表达。大鼠发展为与轻度心肌肥厚相关的动脉高血压（增加 24%）。cAMP-PDE4 活性特异性增加，而 cGMP-PDE 活性广泛增加（PDE1 增加 130%；PDE2 增加 76%；PDE5 增加 113%），同时 PDE1A、PDE1C 和 PDE5A 的表达增加。cGMP-PDE1 的 Ca（2+）/CaM 激活减少。BNP 表达增加了 3.5 倍，而 NOX2 表达减少了 66%，AMP 激酶激活增加了 64%。在血管紧张素 II 诱导的早期左心室肥厚中，左心室中所有特定的 PDE 活性均增加，有利于 PDE1、PDE2 和 PDE5 水解 cGMP 的增加。cAMP 水解的增加与 PDE4 有关。我们观察到两种心脏保护机制的建立，我们认为这些机制可能导致细胞内 cGMP 增加：i）BNP 的增加可能会增加“颗粒”cGMP 池；ii）AMPK 的激活增加，随后 PDE4 活性增加和 5'AMP 生成增加，可能通过下调 NOX2 增加 NO 的生物利用度来升高“可溶性”cGMP 池。需要进一步的研究来支持这些假设。然而，我们的结果表明 PDE4 和 AMPK/NOX2 之间存在潜在联系，并且指出 cGMP-PDE 特别是 PDE1 和 PDE2，可能是预防心肌肥厚的有前途的治疗靶点。
