title: Chronic inhibition of cGMP-specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 Ca(2+) -ATPase activity via phosphorylation of phospholamban at Ser(16) . This may contribute to the attenuation of ER stress induced by PDE5 inhibition.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Quanlu
authors.initials: Q
authors.lastname: Duan
authors.forename: Zhejun
authors.initials: Z
authors.lastname: Cai
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Ni
authors.forename: Mengwen
authors.initials: M
authors.lastname: Yan
authors.forename: Xingxu
authors.initials: X
authors.lastname: Wang
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology / Q000601:surgery; D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D003250:Constriction; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013318:Stroke Volume / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007545:Isoproterenol; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000068677:Sildenafil Citrate; D013450:Sulfones; D000099211:Phospholamban
keywords: ER stress; PDE5; PKG; heart failure
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