Pathological Cardiac Hypertrophy Alters Intracellular Targeting of PDE5 from Nitric Oxide Synthase-3 to Natriuretic Peptide Signaling
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.
- Received January 30, 2012.
- Accepted June 15, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited