Pathological Cardiac Hypertrophy Alters Intracellular Targeting of Phosphodiesterase Type 5 From Nitric Oxide Synthase-3 to Natriuretic Peptide Signaling

Abstract

Background In the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide (specifically from NOS3) but not natriuretic peptide (NP) stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Since NO signaling declines whereas NP-derived cGMP rises in such diseases, we hypothesized that PDE5 substrate selectivity is retargeted to blunt NP-derived signaling. Methods and Results Mice with cardiac myocyte inducible PDE5 overexpression (P5+) were crossed to those lacking NOS3 (N3−), and each model, the double cross, and controls were subjected to transaortic constriction (TAC). P5+ mice developed worse dysfunction and hypertrophy, and enhanced NP stimulation, whereas N3− mice were protected. However, P5+/N3− mice behaved similarly to P5+ despite the lack of NOS3-coupled cGMP generation, with PKG activity suppressed in both models. PDE5 inhibition did not alter ANP-stimulated cGMP in the resting heart, but augmented it in the TAC heart. This functional retargeting was associated with PDE5 translocation from sarcomeres to a dispersed distribution. P5+ hearts exhibited higher oxidative stress whereas P5+/N3− hearts had low levels (likely due to the absence of NOS3 uncoupling). This highlights the importance of myocyte PKG activity as a protection to pathological remodeling. Conclusions These data provide the first evidence for functional retargeting of PDE5 from one compartment to another, revealing a role for NP-derived cGMP hydrolysis by this esterase in diseased heart myocardium. Retargeting likely impacts the pathophysiologic consequence and also therapeutic impact of PDE5 modulation in heart disease.

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

“…This is even more critical when examining phosphodiesterases, which control highly compartmentalized cAMP pools, and redistribution phenomena under pathological conditions have been reported. 52,53 Despite designing our experiments after general recommendations for state-of-the-art phenotyping of transgenic mice, 36 we are not able to fully exclude artificial compartmentation effects. However, the specificity of the phenotype and its striking similarities to in vivo studies of endogenous phosphodiesterase 2 from mice and larger animals offers a valid approach for analyzing the pathophysiological role of phosphodiesterase 2 in heart function.…”

Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network

“…Recent advances have revealed that many signaling components in the network form compartments and/or multi-protein signaling complexes (“signalosomes”) [1, 2, 25, 104–107]. With advancements in methods for spatiotemporally-resolved recording of cAMP [1, 2, 25, 104–107] and cGMP [49, 108, 109], extending the model to include these additional mechanisms is an important next step to understand diversification of cN signals in subcellular micro-domains and communication between these cellular compartments. Under conditions exhibiting high [cGMP], cAMP-cGMP positive cross-talk is likely to be more substantial than that shown in Fig.…”

Volume overload induces differential spatiotemporal regulation of myocardial soluble guanylyl cyclase in eccentric hypertrophy and heart failure

“…3). The PDE isoforms and their splice variants have subcellular regional specificity; PDE2A is confined to the membrane with the sarcomeric Z-band [36], PDE3A isoforms are either cytosolic or membrane-associated [37], and PDE5 localizes to the cardiomyocyte sarcomeric Z-band but becomes diffusely distributed in pathologically hypertrophied hearts [38,39]. Local cGMP pools within cardiomyocytes likely change over time with chronic volume-overload, as the relative expression and subcellular localization of these cardiac PDE isoforms vary along with the relocalization of the sGC subunits, and may mark the transition from compensated eccentric hypertrophy to clinical decompensation.…”