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(Circulation Research. 2007;100:96.)
© 2007 American Heart Association, Inc.

Cellular Biology

Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca²⁺ Cycling

Carlo G. Tocchetti^*, Wang Wang^*, Jeffrey P. Froehlich^*, Sabine Huke, Miguel A. Aon, Gerald M. Wilson, Giulietta Di Benedetto, Brian O’Rourke, Wei Dong Gao, David A. Wink, John P. Toscano, Manuela Zaccolo, Donald M. Bers, Hector H. Valdivia, Heping Cheng, David A. Kass, Nazareno Paolocci

From the Cardiology Division (C.G.T., M.A.A., B.O’R., D.A.K., N.P.) and Division of Anesthesiology and Critical Care Medicine (W.D.G.), Johns Hopkins Medical Institutions, Baltimore, Md; Cardiovascular Sciences Laboratory (W.W., H.C.), National Institute of Aging, NIH, Baltimore, Md; Department of Biochemistry & Molecular Biology (J.P.F., G.M.W.), University of Maryland, Baltimore; Department of Physiology (S.H., D.M.B.), Loyola University Chicago, Maywood, Ill; Dulbecco Telethon Institute (G.D.B., M.Z.), Venetian Institute of Molecular Medicine, Padua, Italy; Radiation Biology Branch (D.A.W.), National Cancer Institute, NIH, Bethesda, Md; Department of Chemistry (J.P.T.), Johns Hopkins University, Baltimore, Md; Department of Physiology (H.H.V.), University of Wisconsin Medical School, Madison; and Institute of Molecular Medicine (H.C.), Peking University, Beijing, China.

Correspondence to Nazareno Paolocci, MD, PhD, Ross Bldg 835, Cardiology Division, Johns Hopkins Medical Institutions, 720 Rutland Ave, Baltimore, MD 21205. E-mail npaoloc1{at}jhmi.edu

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 Ca²⁺. 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 Ca²⁺ pump and the ryanodine receptor 2, leading to increased Ca²⁺ uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca²⁺-release channels and accelerates Ca²⁺ reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca²⁺ 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 Ca²⁺ cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure.

Key Words: nitroxyl • contractility • ryanodine receptor • sarcoplasmic reticulum Ca²⁺-ATPase • excitation/contraction coupling

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