Abstract 561: A Cathepsin D-Cleaved 16kDa Form of Prolactin Mediates Postpartum Cardiomyopathy: Inhibition of Prolactin as a Novel Therapy Option

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Background: Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery despite optimal medical therapy. Mice with a cardiac specific knockout for STAT3 (KO: ∈±-MHC-Cretg/+; stat3flox/flox) develop PPCM. We used KO mice to investigate potential mechanisms behind PPCM and compared our findings to patients with acute PPCM. Methods: Cathepsin D (CD) expression was determined by Western blot and immunohistochemistry in left ventricles (LV) of wildtype (WT: stat3flox/flox) and KO mice after two subsequent pregnancies. In mouse LV supernatant CD activity was analyzed by ELISA and cleavage of recombinant prolactin (Prl) was determined by Western blot. Adenoviruses expressing either the16kDa Prl or as control the LacZ protein were injected into LVs of virgin WT mice. Prl secretion was inhibited by oral administration of bromocriptine in mice (BR, 4mg/kg/day 5 days before till 3 weeks postpartum). In serum samples collected from patients with acute PPCM (n=6) and from healthy nursing women (n=5) Prl isoform expression was analyzed by Western blot and CD activity was measured by ELISA. Results: In LVs from postpartum KO mice CD expression (3x, P<0.05) and activity (4x, P<0.05) was significantly enhanced and was associated with marked generation of the cleaved anti-angiogenic and pro-apoptotic 16kDa form of Prl compared with LVs from postpartum WT mice. Inhibition of Prl secretion by BR prevented the development of PPCM in KO mice completely. In contrast, the forced myocardial generation of 16kDa Prl by adenoviral transfection impaired the cardiac capillary network (−31±12%, P<0.05) and the cardiac function (LacZ: 43±2% vs 16kDa : 33±7%, P<0.05) while no such effect was observed in mice transfected with LacZ expressing adenovirus. In serum probes of patients (n=4) with acute PPCM enhanced CD activity (4x, P<0.05) and elevated levels of 16kDa Prl (2 to 5 times; P<0.05) were observed compared with serum probes of healthy nursing women (n=5). Conclusions: We propose that a biologically active, derivative of the pregnancy hormone, prolactin, mediates PPCM implying that inhibition of Prl release may represent a novel therapeutic strategy for PPCM.