This Article Full Text Full Text (PDF) All Versions of this Article: 1/4/265    most recent CIRCHEARTFAILURE.108.785279v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Toischer, K. Articles by Hasenfuss, G. Search for Related Content PubMed Articles by Toischer, K. Articles by Hasenfuss, G. Related Collections Contractile function Physiological and pathological control of gene expression

Original Articles

Elevated Afterload, Neuroendocrine Stimulation, and Human Heart Failure Increase BNP Levels and Inhibit Preload-Dependent SERCA Upregulation

Karl Toischer, MD; Harald Kögler, MD; Gero Tenderich, MD; Cornelia Grebe, MSc; Tim Seidler, MD; Phuc Nguyen Van, PhD; Klaus Jung, PhD; Ralph Knöll, MD; Reiner Körfer, MD and Gerd Hasenfuss, MD

From the Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Göttingen, Germany (K.J., H.K., C.G., T.S., P.N.V., G.H.); Abteilung Herz- und Thoraxchirurgie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany (G.T., R.K.); and Abteilung Medizinische Statistik (K.J.) and Kardiovaskuläre Molekulargenetik, Herzzentrum, Georg-August-Universität, Göttingen, Germany (R.K.).

Correspondence to Karl Toischer, MD, Abteilung Kardiologie und Pneumologie, Universität Göttingen, Robert-Koch-Str. 40, D – 37075 Göttingen, Germany. E-mail ktoischer{at}med.uni-goettingen.de

Received April 15, 2008; accepted August 26, 2008.

Background— In heart failure, brain-type natriuretic peptide (BNP) is elevated and the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) downregulated. We previously showed that preload-induced SERCA-upregulation is suppressed by exogenous BNP.

Methods and Results— Here we tested the hypothesis that afterload and neurohumoral activation would counterregulate preload-dependent SERCA upregulation through BNP, which finally results in decreased SERCA levels. We studied the effects of 6 hours preload, afterload, and isoproterenol stimulation on BNP and SERCA mRNA expression in rabbit and human failing muscles strips. Preload resulted in a pronounced upregulation of SERCA by 149% (isotonic versus slack, P<0.01). This upregulation was largely suppressed in afterloaded muscles (isometric versus slack: +32%; P<0.05). Similarly, presence of isoproterenol prevented SERCA upregulation in isotonic muscles. Afterload and isoproterenol resulted in a pronounced increase in BNP expression compared with slack by 225% (P<0.05) and 198% (P<0.01), respectively. Isoproterenol also increased expression of phospholamban by 84% (P<0.01). SERCA upregulation in preloaded muscles is associated with frequency-dependent potentiation of contractile force, which is absent in afterloaded muscles. In failing human myocardium, BNP expression was upregulated compared with nonfailing (+631%; P<0.05). Neither unloading nor preload or afterload induced a change in SERCA or BNP expression after 6 hours.

Conclusions— Afterload and neuroendocrine stimulation increase BNP expression thereby causing inhibition of preload-dependent SERCA upregulation. In failing human myocardium, high BNP expression may underlie the loss of preload-dependent upregulation of SERCA. BNP may thus contribute to adverse myocardial remodelling in heart failure.

Key Words: calcium • heart failure • mechanics • natriuretic peptides • sarcoplasmic reticulum

---

 

CLINICAL PERSPECTIVE