title: 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 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.
  
  
  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.
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Manling
authors: M
authors: Zhang
authors: Eiki
authors: E
authors: Takimoto
authors: Dong-ik
authors: DI
authors: Lee
authors: Celio X C
authors: CX
authors: Santos
authors: Taishi
authors: T
authors: Nakamura
authors: Steven
authors: S
authors: Hsu
authors: Aiyang
authors: A
authors: Jiang
authors: Takahiro
authors: T
authors: Nagayama
authors: Djahida
authors: D
authors: Bedja
authors: Yuan
authors: Y
authors: Yuan
authors: Philip
authors: P
authors: Eaton
authors: Ajay M
authors: AM
authors: Shah
authors: David A
authors: DA
authors: Kass
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D009320:Atrial Natriuretic Factor; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006152:Cyclic GMP