Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

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.

Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling

“…Together, the current data allow us to conclude that in the presence of amplified AT 1 R signal transduction in murine CMs and hypertrophic heart disease, potentially beneficial effects of cGMP do not involve SIL/PDE5 directly in these cells (Lukowski et al, 2010Mokni et al, 2010;Degen et al, 2015).…”

“…We examined the potentially antihypertrophic and antifibrotic roles of cGMP signaling for the (Ang II)/AT 1 R-provoked defects in the CM (Booz, 2005), as intensive cross-talk between these pathways in different settings of cardiac stresses has been reported (Li et al, 2002;Masuyama et al, 2006;Tokudome et al, 2008;Klaiber et al, 2010;Mokni et al, 2010;Frantz et al, 2013;Patrucco et al, 2014).…”

Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways

“…For example, in rat aortic vascular smooth muscle cells, ANG II increases PDE5A expression via the AT 1 receptor, ERK1/2 pathway (13). Also, ANG II increases PDE5A mRNA, protein, and enzyme activity in the left cardiac ventricle of rats (22). All of the components of RAAS are present in the kidney, and RT-PCR of microdissected tubules has identified the AT 1 receptor in the cortical, outer medullary, and inner medullary collecting duct (23).…”

Rôle des phosphodiestérases des nucléotides cycliques de types 3 et 4 dans le couplage excitation-contraction et les arythmies cardiaques

“…Les protéines de cette famille de PDE sont codées par quatre gènes différents (PDE4A-D). Selon certains auteurs, seules les PDE4A, PDE4B et PDE4D seraient exprimées dans le tissu cardiaque [25], tandis que d'autres rapportent la présence de transcrits pour la PDE4C dans le coeur [26]. Dans la plupart des espèces, l'inhibition des PDE4 n'exerce peu ou pas d'effet inotrope positif direct, mais devient importante lorsque les taux d'AMPc sont augmentés [16,27].…”

“…Dans un modèle d'hypertrophie pathologique par surcharge de pression chez le rat, nous avons observé une diminution de l'activité PDE totale due à une baisse d'expression et d'activité des PDE3A, PDE4A et PDE4B [38]. En revanche, dans un modèle d'installation d'hypertrophie cardiaque induite par l'angiotensine II, on observe une augmentation d'activité PDE4 accompagnée d'une augmentation d'expression de la PDE4A de 69-kDa et d'une diminution d'expression des PDE4D de 52-et 76-kDa [26]. Ces résultats suggèrent que les niveaux d'expression des isoformes de PDE3 et PDE4 sont régulés de façon spécifique selon le type de stimulus utilisé pour induire l'hypertrophie cardiaque et le stade de la pathologie.…”