Chronic inhibition of cGMP-specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure
Article first published online: 14 NOV 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Neuropeptides. Guest Editors: Julie Keeble
Volume 170, Issue 7, pages 1396–1409, December 2013
How to Cite
Gong, W., Duan, Q., Cai, Z., Chen, C., Ni, L., Yan, M., Wang, X., Cianflone, K. and Wang, D. W. (2013), Chronic inhibition of cGMP-specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure. British Journal of Pharmacology, 170: 1396–1409. doi: 10.1111/bph.12346
- Issue published online: 14 NOV 2013
- Article first published online: 14 NOV 2013
- Accepted manuscript online: 22 AUG 2013 05:51AM EST
- Manuscript Accepted: 12 AUG 2013
- Manuscript Revised: 23 JUL 2013
- Manuscript Received: 28 DEC 2012
- 973 program. Grant Number: 2012CB518004
- NSFC. Grant Numbers: 31130031, 30930039
- ER stress;
- heart failure;
Background and Purpose
Inhibition of the cGMP-specific phosphodiesterase 5 (PDE5) exerts profound beneficial effects on failing hearts. However, the mechanisms underlying the therapeutic effects of PDE5 inhibition on heart failure are unclear. The purpose of this study was to investigate whether PDE5 inhibition decreases endoplasmic reticulum (ER) stress, a key event in heart failure.
Heart failure was induced by isoprenaline s.c. injection in Sprague–Dawley rats and transverse aortic constriction (TAC) in mice. PDE5 was inhibited with sildenafil. Heart function was detected by invasive pressure–volume analysis and echocardiography. ER stress markers were analysed by Western blotting. Apoptosis was measured by flow cytometric analysis.
PDE5 inhibition markedly attenuated isoprenaline-induced and TAC-induced cardiac hypertrophy and dysfunction, and reduced ER stress and apoptosis. Further, PDE5 inhibition with sildenafil largely prevented ER stress and reduced apoptosis in isoprenaline- or thapsigargin-treated cardiomyocytes. PKG inhibition markedly prevented the protective effects of sildenafil in vivo and in vitro. To further understand the mechanism of the effect of PDE5 inhibition on ER stress, we demonstrated that PDE5 inhibitor increased sarco-(endo)-plasmic reticulum Ca2+-ATPase activity via phosphorylation of phospholamban at Ser16. This may contribute to the attenuation of ER stress induced by PDE5 inhibition.
Conclusion and Implications
These results suggest that PDE5 inhibition can attenuate ER stress and improve cardiac function in vivo and in vitro. Suppression of ER stress by inhibiting PDE5 may contribute to the therapeutic effects on heart failure.