title: Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling.
abstract: Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca(2+). A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca(2+) pump and the ryanodine receptor 2, leading to increased Ca(2+) uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca(2+)-release channels and accelerates Ca(2+) reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca(2+) transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca(2+) cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure.
authors.affiliation: Cardiology Division, Johns Hopkins Medical Institutions, 720 Rutland Ave, Baltimore, MD 21205, USA.
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Froehlich
authors.forename: Sabine
authors.initials: S
authors.lastname: Huke
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aon
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Wilson
authors.forename: Giulietta
authors.initials: G
authors.lastname: Di Benedetto
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: John P
authors.initials: JP
authors.lastname: Toscano
authors.forename: Manuela
authors.initials: M
authors.lastname: Zaccolo
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Hector H
authors.initials: HH
authors.lastname: Valdivia
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009573:Nitrites / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D009573:Nitrites; D009589:Nitrogen Oxides; D019837:Ryanodine Receptor Calcium Release Channel; D013438:Sulfhydryl Compounds; C021229:oxyhyponitrite; D000255:Adenosine Triphosphate; D000252:Calcium-Transporting ATPases; C039900:nitroxyl; D002118:Calcium