Chronic inhibition of cGMP‐specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure. (December 2013)

• Record Type: Journal Article
• Authors: Gong, Wei; Duan, Quanlu; Cai, Zhejun; Chen, Chen; Ni, Li; Yan, Mengwen; Wang, Xingxu; Cianflone, Katherine; Wang, Dao Wen
• Is Part Of: British journal of pharmacology. Volume 170:Number 7(2013:Dec.)
• Page Start: 1396
• Page End: 1409
• Publication Date: 2013-12
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12346
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12346-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12346-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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.</p> </sec> <sec id="bph12346-sec-0003" sec-type="section"> <title>Key Results</title> <p>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 <italic>in vivo</italic> and <italic>in vitro</italic>. To further understand the mechanism of the effect of PDE5 inhibition on ER stress, we demonstrated that PDE5 inhibitor increased sarco‐(endo)‐plasmic reticulum Ca<sup>2+</sup>‐ATPase activity via phosphorylation of phospholamban at Ser<sup>16</sup>. This may contribute to the attenuation of ER stress induced by PDE5 inhibition.</p> </sec> <sec id="bph12346-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>These results suggest that PDE5 inhibition can attenuate ER stress and improve cardiac function <italic>in vivo</italic> and <italic>in vitro</italic>. Suppression of ER stress by inhibiting PDE5 may contribute to the therapeutic effects on heart failure.</p> </sec> </abstract>