A Cathepsin D-Cleaved 16 kDa Form of Prolactin Mediates Postpartum Cardiomyopathy
نویسندگان
چکیده
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.
منابع مشابه
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1. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;368:687–93. 2. Corbacho AM, Martinez De La Escalera G, Clapp C. Roles of prolactin and related members of the prolactin/growth hormone/ placental lactogen family in angiogenesis. J Endocrinol 2002;173: 219–38. 3. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpar...
متن کاملRecovery from postpartum cardiomyopathy in 2 patients by blocking prolactin release with bromocriptine.
To the Editor: Postpartum cardiomyopathy (PPCM) is a disease of unknown origin and exposes women to a high risk of mortality after delivery despite optimal medical therapy (1). Prolactin is up-regulated postpartally where it induces lactation and promotes reshaping of the uterus. Prolactin exists in at least 2 biologically active forms with opposing effects. The physiological full-length 23 kDa...
متن کاملRemarks on the Prolactin Hypothesis of Peripartum Cardiomyopathy
A seminal study in 2007 introduced the hypothesis that an antiangiogenic prolactin fragment with a molecular mass of 16 kDa is a key pathological mediator of peripartum cardiomyopathy (PPCM) (1). The study reported that this fragment is enzymatically generated by the cleavage of full-length prolactin with the lysosomal aspartyl protease cathepsin D. Upon excessive generation, possibly due to hi...
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BACKGROUND Peripartum cardiomyopathy (PPCM) is a pregnancy-associated cardiomyopathy in previously healthy women. Mice with a cardiomyocyte-restricted deletion of signal transducer and activator of transcription-3 (STAT3, CKO) develop PPCM. PI3K-Akt signalling is thought to promote cardiac hypertrophy and protection during pregnancy. We evaluated the role of activated Akt signalling in the mate...
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It has been reported that prolactin (PRL) is cleaved to 14 or 16 kDa fragments by cathepsin D in vitro and in vivo, and that such fragments exhibit antiangiogenic and proapoptotic properties. The aim of this study was to investigate the relationship between pregnancy induced hypertension (PIH) and the placental expression of antiangiogenic PRL fragments and cathepsin D. Placental expression of ...
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ورودعنوان ژورنال:
- Cell
دوره 128 شماره
صفحات -
تاریخ انتشار 2007