PDE5 and Retargeting of Subcellular cGMP Signaling During Pathological Hypertrophy
cAMP and cGMP are critical intracellular second messengers regulating fundamental physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression, cell growth and apoptosis and cardiac structural remodeling. cAMP is synthesized by adenylate cyclases upon activation of GPCRs (G-protein-coupled receptors). cGMP is generated from the cytosolic purine nucleotide GTP by guanylate cylases (GCs) using Mg2+ or Mn2+ as cofactors. Two isoforms of GCs exist in vertebrate cells and tissues: a nitric oxide (NO)-sensitive cytosolic or soluble GC (sGC) and atrial natriuretic peptides (NP) activated plasma membrane bound, particulate GC (pGC).1 Once produced, the effects of cGMP occur through three main groups of cellular target molecules: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels and phosphodiesterases (PDEs). PDEs are metallohydrolases that catalyze the breakdown of cAMP or cGMP into the inactive 5′-AMP, thus modulating the duration and the intensity of their intracellular response. PDEs have 11 families (PDE1-11) which are encoded by 21 different genes. More than 80 enzyme variants are generated from multiple promoters and as a consequence of alternative splicing2. (SELECT FULL TEXT TO CONTINUE)
- atrial natriuretic factor
- nitric oxide synthase
- oxidative stress
- phosphodiesterase inhibitors heart failure
- Received July 16, 2012.
- Accepted July 18, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited