Abstract
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 Ca2+/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.
Highlights
Left ventricular hypertrophy is a major risk factor for premature death [1]
Since no studies were done investigating simultaneously the various cAMP- and cGMP-PDE isoform contributions in cardiac pathology, we aimed to explore the variations of PDE1 to PDE5 in left cardiac ventricle on a rat model of cardiac hypertrophy induced by angiotensin II, and especially in the initial stages of cardiac hypertrophy development
The present results in left cardiac ventricles of control rats are consistent with those data, and they highlight the importance of cardiac cAMP catabolism in regulating cardiac contractility
Summary
Left ventricular hypertrophy is a major risk factor for premature death [1]. There is a correlation between plasmatic angiotensin II, hypertension, development of cardiac hypertrophy [2] and remodeling leading to heart failure [3]. Cyclic nucleotides play a major role in the activation of different intracellular signaling pathways. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and/ or cGMP, regulate contractility in response to different stimuli such as b-adrenergic receptors [6] and natriuretic peptide receptors [7] and participate to cardiac remodeling [8]. PDE1A and PDE1B hydrolyze mainly cGMP, while PDE1C hydrolyzes cAMP and cGMP. PDE2 hydrolyzes cGMP and cAMP, and its cAMP hydrolysis is allosterically activated by cGMP [10]. CGMP has a greater affinity for PDE3 while being hydrolyzed 10 times slower than cAMP, which makes it acts as a PDE3 inhibitor. PDE4 hydrolyzes cAMP and could be activated subsequently through PKA-dependent phosphorylation while PDE5 hydrolyzes cGMP and could be activated by cGMP and PKG-dependent phosphorylation [11]
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