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

Manling Zhang, Eiki Takimoto, Dong-ik Lee, Celio Santos Xavier Da Costa Dos Santos, Taishi Nakamura, Steven Hsu, Aiyang Jiang, Takahiro Nagayama, Djahida Bedja, Yuan Yuan, Philip Eaton, Ajay M. Shah, David A. Kass

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Background-In the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide-(specifically from nitric oxide synthase 3) but not natriuretic peptide (NP)-stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Because nitric oxide 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 nitric oxide synthase 3 (N3(-)), and each model, the double cross, and controls were subjected to transaortic constriction. P5(+) mice developed worse dysfunction and hypertrophy and enhanced NP stimulation, whereas N3(-) mice were protected. However, P5(+)/N3(-) mice behaved similarly to P5(+) mice despite the lack of nitric oxide synthase 3-coupled cGMP generation, with protein kinase G activity suppressed in both models. PDE5 inhibition did not alter atrial natriuretic peptide-stimulated cGMP in the resting heart but augmented it in the transaortic constriction 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 owing to the absence of nitric oxide synthase 3 uncoupling). This highlights the importance of myocyte protein kinase G activity as a protection for pathological remodeling.

Conclusions-These data provide the first evidence for functional retargeting of PDE5 from one compartment to another, revealing a role for natriuretic peptide-derived cGMP hydrolysis by this esterase in diseased heart myocardium. Retargeting likely affects the pathophysiological consequence and the therapeutic impact of PDE5 modulation in heart disease. (Circulation. 2012;126:942-951.)

Original languageEnglish
Pages (from-to)942-U96
Number of pages19
JournalCirculation (Baltimore)
Volume126
Issue number8
Early online date24 Jul 2012
DOIs
Publication statusPublished - 21 Aug 2012

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