• Medientyp: E-Artikel
  • Titel: Cardiomyocyte Overexpression of Neuronal Nitric Oxide Synthase Delays Transition Toward Heart Failure in Response to Pressure Overload by Preserving Calcium Cycling
  • Beteiligte: Loyer, Xavier; Gómez, Ana Maria; Milliez, Paul; Fernandez-Velasco, Maria; Vangheluwe, Peter; Vinet, Laurent; Charue, Dominique; Vaudin, Emilie; Zhang, Wei; Sainte-Marie, Yannis; Robidel, Estelle; Marty, Isabelle; Mayer, Bernd; Jaisser, Frédéric; Mercadier, Jean-Jacques; Richard, Sylvain; Shah, Ajay M.; Bénitah, Jean-Pierre; Samuel, Jane-Lise; Heymes, Christophe
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2008
  • Erschienen in: Circulation
  • Umfang: 3187-3198
  • Sprache: Englisch
  • DOI: 10.1161/circulationaha.107.741702
  • ISSN: 0009-7322; 1524-4539
  • Schlagwörter: Physiology (medical) ; Cardiology and Cardiovascular Medicine
  • Zusammenfassung: <jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Defects in cardiomyocyte Ca <jats:sup>2+</jats:sup> cycling are a signature feature of heart failure (HF) that occurs in response to sustained hemodynamic overload, and they largely account for contractile dysfunction. Neuronal nitric oxide synthase (NOS1) influences myocyte excitation-contraction coupling through modulation of Ca <jats:sup>2+</jats:sup> cycling, but the potential relevance of this in HF is unknown. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> We generated a transgenic mouse with conditional, cardiomyocyte-specific NOS1 overexpression (double-transgenic [DT]) and studied cardiac remodeling, myocardial Ca <jats:sup>2+</jats:sup> handling, and contractility in DT and control mice subjected to transverse aortic constriction (TAC). After TAC, control mice developed eccentric hypertrophy with evolution toward HF as revealed by a significantly reduced fractional shortening. In contrast, DT mice developed a greater increase in wall thickness ( <jats:italic>P</jats:italic> &lt;0.0001 versus control+TAC) and less left ventricular dilatation than control+TAC mice ( <jats:italic>P</jats:italic> &lt;0.0001 for both end-systolic and end-diastolic dimensions). Thus, DT mice displayed concentric hypertrophy with fully preserved fractional shortening (43.7±0.6% versus 30.3±2.6% in control+TAC mice, <jats:italic>P</jats:italic> &lt;0.05). Isolated cardiomyocytes from DT+TAC mice had greater shortening, intracellular Ca <jats:sup>2+</jats:sup> transients, and sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> load ( <jats:italic>P</jats:italic> &lt;0.05 versus control+TAC for all parameters). These effects could be explained, at least in part, through modulation of phospholamban phosphorylation status. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> Cardiomyocyte NOS1 may be a useful target against cardiac deterioration during chronic pressure-overload–induced HF through modulation of calcium cycling. </jats:p>
  • Beschreibung: <jats:p>
    <jats:bold>
    <jats:italic>Background—</jats:italic>
    </jats:bold>
    Defects in cardiomyocyte Ca
    <jats:sup>2+</jats:sup>
    cycling are a signature feature of heart failure (HF) that occurs in response to sustained hemodynamic overload, and they largely account for contractile dysfunction. Neuronal nitric oxide synthase (NOS1) influences myocyte excitation-contraction coupling through modulation of Ca
    <jats:sup>2+</jats:sup>
    cycling, but the potential relevance of this in HF is unknown.
    </jats:p>
    <jats:p>
    <jats:bold>
    <jats:italic>Methods and Results—</jats:italic>
    </jats:bold>
    We generated a transgenic mouse with conditional, cardiomyocyte-specific NOS1 overexpression (double-transgenic [DT]) and studied cardiac remodeling, myocardial Ca
    <jats:sup>2+</jats:sup>
    handling, and contractility in DT and control mice subjected to transverse aortic constriction (TAC). After TAC, control mice developed eccentric hypertrophy with evolution toward HF as revealed by a significantly reduced fractional shortening. In contrast, DT mice developed a greater increase in wall thickness (
    <jats:italic>P</jats:italic>
    &lt;0.0001 versus control+TAC) and less left ventricular dilatation than control+TAC mice (
    <jats:italic>P</jats:italic>
    &lt;0.0001 for both end-systolic and end-diastolic dimensions). Thus, DT mice displayed concentric hypertrophy with fully preserved fractional shortening (43.7±0.6% versus 30.3±2.6% in control+TAC mice,
    <jats:italic>P</jats:italic>
    &lt;0.05). Isolated cardiomyocytes from DT+TAC mice had greater shortening, intracellular Ca
    <jats:sup>2+</jats:sup>
    transients, and sarcoplasmic reticulum Ca
    <jats:sup>2+</jats:sup>
    load (
    <jats:italic>P</jats:italic>
    &lt;0.05 versus control+TAC for all parameters). These effects could be explained, at least in part, through modulation of phospholamban phosphorylation status.
    </jats:p>
    <jats:p>
    <jats:bold>
    <jats:italic>Conclusions—</jats:italic>
    </jats:bold>
    Cardiomyocyte NOS1 may be a useful target against cardiac deterioration during chronic pressure-overload–induced HF through modulation of calcium cycling.
    </jats:p>
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