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NOS1 induces NADPH oxidases and impairs contraction kinetics in aged murine ventricular myocytes

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Abstract

Nitric oxide (NO) modulates calcium transients and contraction of cardiomyocytes. However, it is largely unknown whether NO contributes also to alterations in the contractile function of cardiomyocytes during aging. Therefore, we analyzed the putative role of nitric oxide synthases and NO for the age-related alterations of cardiomyocyte contraction. We used C57BL/6 mice, nitric oxide synthase 1 (NOS1)-deficient mice (NOS1−/−) and mice with cardiomyocyte-specific NOS1-overexpression to analyze contractions, calcium transients (Indo-1 fluorescence), acto-myosin ATPase activity (malachite green assay), NADPH oxidase activity (lucigenin chemiluminescence) of isolated ventricular myocytes and cardiac gene expression (Western blots, qPCR). In C57BL/6 mice, cardiac expression of NOS1 was upregulated by aging. Since we found a negative regulation of NOS1 expression by cAMP in isolated cardiomyocytes, we suggest that reduced efficacy of β-adrenergic signaling that is evident in aged hearts promotes upregulation of NOS1. Shortening and relengthening of cardiomyocytes from aged C57BL/6 mice were decelerated, but were normalized by pharmacological inhibition of NOS1/NO. Cardiomyocytes from NOS1−/− mice displayed no age-related changes in contraction, calcium transients or acto-myosin ATPase activity. Aging increased cardiac expression of NADPH oxidase subunits NOX2 and NOX4 in C57BL/6 mice, but not in NOS1−/− mice. Similarly, cardiac expression of NOX2 and NOX4 was upregulated in a murine model with cardiomyocyte-specific overexpression of NOS1. We conclude that age-dependently upregulated NOS1, putatively via reduced efficacy of β-adrenergic signaling, induces NADPH oxidases. By increasing nitrosative and oxidative stress, both enzyme systems act synergistically to decelerate contraction of aged cardiomyocytes.

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Acknowledgments

The work was supported by the Roux Program of the Medical Faculty of the Martin Luther University Halle-Wittenberg (FKZ 16/13 to U.R.).

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Authors and Affiliations

  1. Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 6, 06112, Halle (Saale), Germany

    Marten Villmow, Udo Klöckner, Michael Gekle & Uwe Rueckschloss

  2. Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès, 31432, Toulouse Cedex 4, France

    Christophe Heymes

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  1. Marten Villmow
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  2. Udo Klöckner
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  4. Michael Gekle
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  5. Uwe Rueckschloss
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Correspondence to Uwe Rueckschloss.

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Villmow, M., Klöckner, U., Heymes, C. et al. NOS1 induces NADPH oxidases and impairs contraction kinetics in aged murine ventricular myocytes. Basic Res Cardiol 110, 48 (2015). https://doi.org/10.1007/s00395-015-0506-5

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