A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy.
Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.
Hilfiker-Kleiner
Denise
D
Department of Cardiology and Angiology, MHH, 30625 Hannover, Germany. hilfiker.denise@mh-hannover.de
Kaminski
Karol
K
Podewski
Edith
E
Bonda
Tomasz
T
Schaefer
Arnd
A
Sliwa
Karen
K
Forster
Olaf
O
Quint
Anja
A
Landmesser
Ulf
U
Doerries
Carola
C
Luchtefeld
Maren
M
Poli
Valeria
V
Schneider
Michael D
MD
Balligand
Jean-Luc
JL
Desjardins
Fanny
F
Ansari
Aftab
A
Struman
Ingrid
I
Nguyen
Ngoc Q N
NQ
Zschemisch
Nils H
NH
Klein
Gunnar
G
Heusch
Gerd
G
Schulz
Rainer
R
Hilfiker
Andres
A
Drexler
Helmut
H
D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000378:metabolism* / Q000517:prevention & control; D002402:Cathepsin D / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D017379:Hypertrophy, Left Ventricular; D007774:Lactation / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000097:blood; D049590:Postpartum Period / Q000378:metabolism; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000378:metabolism* / Q000517:prevention & control; D011388:Prolactin / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D011644:Puerperal Disorders / Q000378:metabolism* / Q000517:prevention & control; D050796:STAT3 Transcription Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C099252:oxidized low density lipoprotein; C503760:prolactin 16-kDa fragment, human; D001971:Bromocriptine; D011388:Prolactin; D002402:Cathepsin D