Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond.
作者： Robert Lukowski , Thomas Krieg , Sergei D Rybalkin , Joseph Beavo , Franz Hofmann
DOI: 10.1016/J.TIPS.2014.05.003
关键词: Muscle hypertrophy 、 Fibrosis 、 cGMP-dependent protein kinase 、 Cellular localization 、 Protein kinase A 、 Biology 、 Sildenafil 、 Cardioprotection 、 Pharmacology 、 cGMP-specific phosphodiesterase type 5
摘要: cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in but do implicate cGMP-cGKI signaling fibrosis I/R No direct cGKI activators advanced to clinical trials, whereas trials of agents that modulate via particulate or soluble guanylyl cyclases (GCs) phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical question whether targeting the pathway remains an encouraging concept management heart dysfunction. So far, trial results GC modulators inconclusive, sildenafil, PDE5 inhibitor, although cardioprotective mouse models, has shown positive results. Preclinical cardioprotection observed sildenafil may result inhibition non-cardiomyocytes off-target effects, possibly on PDE1C. On basis such mechanistic considerations, re-evaluation cellular localization drug target(s) intervention protocols cGMP-elevating be needed.
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