Abstract Phosphodiesterase type 5 (PDE5) expression is upregulated in human failing heart, and overexpression of PDE5 in transgenic mice exacerbates stress-induced left-ventricular dysfunction, suggesting that increased PDE5 expression might contribute to the development of congestive heart failure. However, the underlying mechanisms for increased PDE5 expression are not totally understood. In the present study, we found that PDE5 activity and expression were regulated by S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO). S-nitrosylation of PDE5 occurs at Cys220, which is located in the GAFA domain. Upon S-nitrosylation, PDE5 exhibits reduced activity and degradation via the ubiquitin-proteasome system. The decrease in PDE5 expression induced by NO could be blunted by mutation of Cys220 or the phosphorylation site of PDE5 (S102), as well as by pretreatment with H2O2. Conversely, decreased NO bioavailability by nitric oxide synthase (NOS) inhibitors or knockout of NOS3 increased PDE5 expression in cardiomyocytes. Collectively, to the best of our knowledge, our data demonstrate for the first time that S-nitrosylation is one of the mechanisms for PDE5 degradation. This novel regulatory mechanism probably accounts for the increase in PDE5 in the failing heart and other diseases in which NO bioavailability is decreased by oxidative stress.
|Original language||English (US)|
|Number of pages||9|
|Journal||Free Radical Biology and Medicine|
|State||Published - Jul 25 2015|
- Free radicals
- Heart failure
- Oxidative stress