Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression.
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.


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.
Kögler
Harald
H
Abteilung für Kardiologie, Georg August Universität, Göttingen, Germany. hkogler@med.uni-goettingen.de
Schott
Peter
P
Toischer
Karl
K
Milting
Hendrik
H
Van
Phuc Nguyen
PN
Kohlhaas
Michael
M
Grebe
Cornelia
C
Kassner
Astrid
A
Domeier
Erik
E
Teucher
Nils
N
Seidler
Tim
T
Knöll
Ralph
R
Maier
Lars S
LS
El-Banayosy
Aly
A
Körfer
Reiner
R
Hasenfuss
Gerd
G
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000502:physiology; D000328:Adult; D000818:Animals; D019703:Calcineurin / Q000502:physiology; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000150:complications; D015331:Cohort Studies; D006152:Cyclic GMP / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D006353:Heart-Assist Devices; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications; D009206:Myocardium / Q000201:enzymology; D050778:NFATC Transcription Factors / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013314:Stress, Mechanical
D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D020097:Natriuretic Peptide, Brain; D019703:Calcineurin; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D000252:Calcium-Transporting ATPases; D006152:Cyclic GMP