Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice.

Zhang, Y; Zhang, M; Sears, C; Emanuel, K; Redwood, C; El-Armouche, A; Kranias, E; Casadei, B

Journal article

Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice.

Abstract:: Stimulation of nitric oxide (NO) release from the coronary endothelium facilitates myocardial relaxation via a cGMP-dependent reduction in myofilament Ca2+ 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 (TR50) and the rate of [Ca2+]i transient decay (tau) are significantly prolonged in field-stimulated or voltage-clamped left ventricular myocytes from nNOS-/- mice and in wild-type myocytes (nNOS+/+) after acute nNOS inhibition. Disabling the sarcoplasmic reticulum abolished the differences in TR50 and tau, suggesting that impaired sarcoplasmic reticulum Ca2+ reuptake may account for the slower relaxation in nNOS-/- mice. In line with these findings, disruption of nNOS (but not of endothelial NOS) decreased phospholamban phosphorylation (P-Ser16 PLN), whereas nNOS inhibition had no effect on TR50 or tau in PLN-/- 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-Ser16 PLN and prolonging TR50 in nNOS+/+ myocytes. Conversely, inhibition of type 1 or 2A protein phosphatases shortened TR50 and increased P-Ser16 PLN in nNOS-/- but not in nNOS+/+ myocytes, in agreement with data showing increased protein phosphatase activity in nNOS-/- 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 Ca2+ reuptake via a cGMP-independent effect on protein phosphatase activity.

Publication status:: Published

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APA Style

Zhang, Y., Zhang, M., Sears, C., Emanuel, K., Redwood, C., El-Armouche, A., Kranias, E., & Casadei, B. (2008). Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice. Circulation Research, 102(2), 242–249.

MLA Style

Zhang, Y., et al. “Reduced Phospholamban Phosphorylation Is Associated with Impaired Relaxation in Left Ventricular Myocytes from Neuronal NO Synthase-Deficient Mice.” Circulation Research, vol. 102, no. 2, 2008, pp. 242–49.

Chicago Style

Zhang, Y, M Zhang, C Sears, K Emanuel, C Redwood, A El-Armouche, E Kranias, and B Casadei. 2008. “Reduced Phospholamban Phosphorylation Is Associated with Impaired Relaxation in Left Ventricular Myocytes from Neuronal NO Synthase-Deficient Mice.” Circulation Research 102 (2): 242–49.
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