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(Circulation. 2006;113:2724-2732.)
© 2006 American Heart Association, Inc.

Heart Failure

Relevance of Brain Natriuretic Peptide in Preload-Dependent Regulation of Cardiac Sarcoplasmic Reticulum Ca²⁺ ATPase Expression

Harald Kögler, MD^*; Peter Schott, MD^*; Karl Toischer, MD; Hendrik Milting, PhD; Phuc Nguyen Van, PhD; Michael Kohlhaas, MSc; Cornelia Grebe, MSc; Astrid Kassner, MSc; Erik Domeier, MD; Nils Teucher, MD; Tim Seidler, MD; Ralph Knöll, MD; Lars S. Maier, MD; Aly El-Banayosy, MD; Reiner Körfer, MD, PhD; Gerd Hasenfuss, MD

From Abteilung für Kardiologie, Georg August Universität, Göttingen (H.K., P.S., K.T., P.N.V., M.K., C.G., E.D., N.T., T.S., R. Knöll, L.S.M., G.H.); and Erich und Hanna Klessmann Institut für Kardiovaskuläre Forschung und Entwicklung (H.M., A.K., A.E.-B., R. Körfer), Herz und Diabeteszentrum NRW, Bad Oeynhausen, Germany.

Correspondence to Harald Kögler, MD, Abteilung für Kardiologie, Universität Göttingen, Robert-Koch-Strasse 40, D–37075 Göttingen, Germany. E-mail hkogler{at}med.uni-goettingen.de

Received April 29, 2005; de novo received December 21, 2005; revision received February 6, 2006; accepted March 24, 2006.

Background— In heart failure (HF), ventricular myocardium expresses brain natriuretic peptide (BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis.

Methods and Results— We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% (n=8) compared with unloaded preparations (n=8; P<0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients (350 pg/mL) abolished SERCA upregulation by stretch (n=9; P<0.0001 versus BNP free). Inhibition of cyclic guanosine 3',5' monophosphate (cGMP)–phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation (n=15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP.

Conclusions— Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.

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