Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Sivakumaran, V; Stanley, BA; Tocchetti, CG; Ballin, JD; Caceres, V; Zhou, L; Keceli, G; Rainer, PP; Lee, DI; Huke, S; Ziolo, MT; Kranias, EG; Toscano, JP; Wilson, GM; O'Rourke, B; Kass, DA; Mahaney, JE; Paolocci, N.
HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization.
Antioxid Redox Signal. 2013; 19(11):1185-1197
Doi: 10.1089/ars.2012.5057
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- Co-Autor*innen der Med Uni Graz
- Rainer Peter
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- Abstract:
- Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca(2+) uptake and myofilament Ca(2+) sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in a redox-dependent manner, improving Ca(2+) handling in isolated myocytes/hearts. Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln(-/-)) mice. Compared to WT, pln(-/-) myocytes displayed enhanced resting sarcomere shortening, peak Ca(2+) transient, and blunted β-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca(2+) transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln(-/-) cells/hearts. HNO enhanced SR Ca(2+) uptake in WT but not pln(-/-) SR-vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a±PLN showed that HNO increased Ca(2+)-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available. HNO-dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a. PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca(2+) handling in failing hearts.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenosine Triphosphate - metabolism
- Animals -
- Antioxidants - pharmacology
- Calcium - metabolism
- Calcium Signaling - drug effects
- Calcium-Binding Proteins - chemistry
- Cardiotonic Agents - pharmacology
- Cyclic AMP-Dependent Protein Kinases - metabolism
- Disulfides -
- Heart Ventricles - drug effects
- In Vitro Techniques -
- Mice -
- Mice, Knockout -
- Microsomes - metabolism
- Myocytes, Cardiac - drug effects
- Nitrogen Oxides - pharmacology
- Oxidation-Reduction - drug effects
- Phosphorylation -
- Protein Binding -
- Protein Conformation - drug effects
- Protein Interaction Domains and Motifs -
- Protein Multimerization - drug effects
- Protein Stability - drug effects
- Sarcoplasmic Reticulum - metabolism
- Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry