Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase–Deficient Mice
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- Yin Hua Zhang
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Mei Hua Zhang
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Claire E. Sears
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Krzysztof Emanuel
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Charles Redwood
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Ali El-Armouche
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Evangelia G. Kranias
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
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- Barbara Casadei
- From the Department of Cardiovascular Medicine (Y.H.Z., M.H.Z., C.E.S., K.E., C.R., B.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Institute of Experimental and Clinical Pharmacology (A.E.-A.), University Hospital Eppendorf, Hamburg, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Ohio.
抄録
<jats:p> Stimulation of nitric oxide (NO) release from the coronary endothelium facilitates myocardial relaxation via a cGMP-dependent reduction in myofilament Ca <jats:sup>2+</jats:sup> sensitivity. Recent evidence suggests that NO released by a neuronal NO synthase (nNOS) in the myocardium can also hasten left ventricular relaxation; however, the mechanism underlying these findings is uncertain. Here we show that both relaxation (TR <jats:sub>50</jats:sub> ) and the rate of [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> transient decay (tau) are significantly prolonged in field-stimulated or voltage-clamped left ventricular myocytes from nNOS <jats:sup>−/−</jats:sup> mice and in wild-type myocytes (nNOS <jats:sup>+/+</jats:sup> ) after acute nNOS inhibition. Disabling the sarcoplasmic reticulum abolished the differences in TR <jats:sub>50</jats:sub> and tau, suggesting that impaired sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> reuptake may account for the slower relaxation in nNOS <jats:sup>−/−</jats:sup> mice. In line with these findings, disruption of nNOS (but not of endothelial NOS) decreased phospholamban phosphorylation (P-Ser <jats:sup>16</jats:sup> PLN), whereas nNOS inhibition had no effect on TR <jats:sub>50</jats:sub> or tau in PLN <jats:sup>−/−</jats:sup> myocytes. Inhibition of cGMP signaling had no effect on relaxation in either group whereas protein kinase A inhibition abolished the difference in relaxation and PLN phosphorylation by decreasing P-Ser <jats:sup>16</jats:sup> PLN and prolonging TR <jats:sub>50</jats:sub> in nNOS <jats:sup>+/+</jats:sup> myocytes. Conversely, inhibition of type 1 or 2A protein phosphatases shortened TR <jats:sub>50</jats:sub> and increased P-Ser <jats:sup>16</jats:sup> PLN in nNOS <jats:sup>−/−</jats:sup> but not in nNOS <jats:sup>+/+</jats:sup> myocytes, in agreement with data showing increased protein phosphatase activity in nNOS <jats:sup>−/−</jats:sup> hearts. Taken together, our findings identify a novel mechanism by which myocardial nNOS promotes left ventricular relaxation by regulating the protein kinase A–mediated phosphorylation of PLN and the rate of sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> reuptake via a cGMP-independent effect on protein phosphatase activity. </jats:p>
収録刊行物
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- Circulation Research
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Circulation Research 102 (2), 242-249, 2008-02
Ovid Technologies (Wolters Kluwer Health)