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 high pituitary prolactin secretion near term or postpartum and an enhanced oxidative microenvironment, this prolactin fragment would impair myocardial microvascularization and thereby contribute to myocardial dysfunction. Accordingly, a new therapy for PPCM was explored using the dopamine D2 receptor agonists, cabergoline and bromocriptine. Treatment with bromocriptine is currently being evaluated in a multicenter clinical trial (NCT00998556) (2). The concept underlying this putative therapy is the inhibition of the generation of the prolactin fragment by substrate depletion, i.e., the inhibition of pituitary prolactin secretion by activation of dopamine D2 receptors in lactotropes. PPCM is a rare disease which occurred with a frequency of 1 case/3189 live births and an estimated mortality of 1.36–2.05% (confidence interval 0.29–10.8%) from 1990 to 2002 in the United States (3). However, the incidence of PPCM seems to be variable, depending on the geographical region, ethnic background, and other criteria (4, 5).
Since the initial discovery, several research, case report, and review articles have been published (5–10) describing signaling mechanisms mediating the deleterious action of the 16-kDa prolactin fragment and supporting the beneficial effects of treatment with dopamine D2 agonists in patients with PPCM. However, there are relevant aspects to the proposed pathological mechanism in PPCM that are absent in these studies with the consequence of limiting the field by pointing to wrong, or incomplete conclusions.
In contrast to what is suggested in most of the PPCM-related literature, the 16-kDa prolactin fragment is only one of the several antiangiogenic prolactin fragments derived from prolactin via cathepsin D and other proteolytic enzymes. Altogether, these fragments of different molecular masses comprise a family of proteins termed vasoinhibins (11, 12). Cathepsin D alone can generate four more vasoinhibins by cleaving full-length prolactin at sites other than the one generating the 16-kDa fragment (13). Three of these cathepsin D-generated vasoinhibin isoforms have documented antiangiogenic activity (11, 13)—a notion that should not go unnoticed when studying the 16-kDa vasoinhibin isoform as a key pathologic mediator of PPCM. The possible contribution of other vasoinhibin isoforms to the pathophysiology of PPCM has neither been investigated nor discussed, not to mention the vasoinhibin isoforms generated by other proteolytic enzymes up regulated in experimental PPCM, such as matrix metalloproteinases (1, 11).
The term “16 kDa PRL” (referring to prolactin as the precursor of the fragment) that has often been used in the PPCM-related literature was updated by the vasoinhibin nomenclature in 2006 (11, 12, 14), and this nomenclature has been refined and reevaluated since then (15–17). The introduction of the vasoinhibin nomenclature was triggered by the recognition that the 16-kDa fragment is not the only endogenous prolactin fragment with antiangiogenic properties. As their functional and structural features are unique and contrast with those of full-length prolactin, it was recognized that these fragments are individual hormones and may not bear the same designation. In consequence they were collectively named “vasoinhibins,” inspired by one of their principal effects, the inhibition of blood vessel growth, and control of blood vessel function.
Another neglected issue concerns the levels of vasoinhibins and the total composition of their isoforms in the circulation during healthy and disease states. In the absence of a quantitative vasoinhibin assay, neither reference ranges nor levels in disease states could be established. Yet, this is required to confirm the contribution of the 16-kDa vasoinhibin isoform to the pathophysiology of PPCM. Higher levels of 16-kDa vasoinhibin would be expected at the onset and declining levels during regression of PPCM. This also concerns the safety of using dopamine agonists to inhibit the generation of vasoinhibins. It should be acknowledged that inhibiting vasoinhibin generation constitutes an intervention into a complex endocrine axis [the prolactin/vasoinhibin axis (18)], which could lead to unintended side effects. Some of the cardiovascular side effects of bromocriptine such as syncope, hypotension, and pleural/pericardial effusion could be influenced by a decline of vasoinhibin levels. This is a possibility as vasoinhibins feature inhibition of vasodilation and vasopermeability (15, 16, 18).
We suggest that whenever the role of the vasoinhibins in PPCM is investigated, their serum levels should be evaluated. This is possible by an established methodology combining immunoprecipitation and western blotting (semi-quantitative) (19). Ideally, at some point in the future, a quantitative vasoinhibin assay could be developed which should then be used to confirm altered levels of vasoinhibin isoforms in PPCM. Although dopamine agonists have been used during pregnancy, the safety of this intervention should carefully be monitored. This is particularly relevant on the background that vasoinhibins are pleiotropic hormones which control angiogenesis-mediated growth in reproductive and non-reproductive organs (18); regulate blood vessel growth, vasopermeability, and vasodilation (15, 16); and have non-vascular effects, which include stimulation of vasopressin release (20), thrombolytic effects (21), and the stimulation of anxiety- and depression-related behaviors (22).
Statements
Author contributions
JT drafted the manuscript. CC, GE, and TB revised the manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
Hilfiker-KleinerDKaminskiKPodewskiEBondaTSchaeferASliwaKet alA cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell (2007) 128(3):589–600.10.1016/j.cell.2006.12.036
2
HaghikiaAPodewskiEBerlinerDSonnenscheinKFischerDAngermannCEet alRationale and design of a randomized, controlled multicentre clinical trial to evaluate the effect of bromocriptine on left ventricular function in women with peripartum cardiomyopathy. Clin Res Cardiol (2015) 104(11):911–7.10.1007/s00392-015-0869-5
3
MielniczukLMWilliamsKDavisDRTangASLemeryRGreenMSet alFrequency of peripartum cardiomyopathy. Am J Cardiol (2006) 97(12):1765–8.10.1016/j.amjcard.2006.01.039
4
BrarSSKhanSSSandhuGKJorgensenMBParikhNHsuJWet alIncidence, mortality, and racial differences in peripartum cardiomyopathy. Am J Cardiol (2007) 100(2):302–4.10.1016/j.amjcard.2007.02.092
5
Hilfiker-KleinerDSliwaK. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat Rev Cardiol (2014) 11(6):364–70.10.1038/nrcardio.2014.37
6
HalkeinJTabruynSPRicke-HochMHaghikiaANguyenNQScherrMet almicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest (2013) 123(5):2143–54.10.1172/JCI64365
7
MeloMACarvalhoJSFeitosaFEAraujo JuniorEPeixotoABCosta CarvalhoFHet alPeripartum cardiomyopathy treatment with dopamine agonist and subsequent pregnancy with a satisfactory outcome. Rev Bras Ginecol Obstet (2016) 38(6):308–13.10.1055/s-0036-1584567
8
AranyZElkayamU. Peripartum cardiomyopathy. Circulation (2016) 133(14):1397–409.10.1161/CIRCULATIONAHA.115.020491
9
BelloNAAranyZ. Molecular mechanisms of peripartum cardiomyopathy: a vascular/hormonal hypothesis. Trends Cardiovasc Med (2015) 25(6):499–504.10.1016/j.tcm.2015.01.004
10
BernardVYoungJChansonPBinartN. New insights in prolactin: pathological implications. Nat Rev Endocrinol (2015) 11(5):265–75.10.1038/nrendo.2015.36
11
MacotelaYAguilarMBGuzman-MoralesJRiveraJCZermenoCLopez-BarreraFet alMatrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin. J Cell Sci (2006) 119(Pt 9):1790–800.10.1242/jcs.02887
12
ClappCArandaJGonzalezCJeziorskiMCMartinez de la EscaleraG. Vasoinhibins: endogenous regulators of angiogenesis and vascular function. Trends Endocrinol Metab (2006) 17(8):301–7.10.1016/j.tem.2006.08.002
13
PiwnicaDTourainePStrumanITabruynSBolbachGClappCet alCathepsin D processes human prolactin into multiple 16K-like N-terminal fragments: study of their antiangiogenic properties and physiological relevance. Mol Endocrinol (2004) 18(10):2522–42.10.1210/me.2004-0200
14
ClappCGonzalezCMacotelaYArandaJRiveraJCGarciaCet alVasoinhibins: a family of N-terminal prolactin fragments that inhibit angiogenesis and vascular function. Front Horm Res (2006) 35:64–73.10.1159/000094309
15
ClappCThebaultSMacotelaYMoreno-CarranzaBTriebelJMartinez de la EscaleraG. Regulation of blood vessels by prolactin and vasoinhibins. Adv Exp Med Biol (2015) 846:83–95.10.1007/978-3-319-12114-7_4
16
ClappCThebaultSJeziorskiMCMartinez De La EscaleraG. Peptide hormone regulation of angiogenesis. Physiol Rev (2009) 89(4):1177–215.10.1152/physrev.00024.2009
17
TriebelJBertschTMartinez de la EscaleraGClappC. On the path toward classifying hormones of the vasoinhibin-family. Front Endocrinol (2015) 6:16.10.3389/fendo.2015.00016
18
TriebelJBertschTBollheimerCRios-BarreraDPearceCFHufnerMet alPrinciples of the prolactin/vasoinhibin axis. Am J Physiol Regul Integr Comp Physiol (2015) 309(10):R1193–203.10.1152/ajpregu.00256.2015
19
GonzalezCParraARamirez-PeredoJGarciaCRiveraJCMacotelaYet alElevated vasoinhibins may contribute to endothelial cell dysfunction and low birth weight in preeclampsia. Lab Invest (2007) 87(10):1009–17.10.1038/labinvest.3700662
20
MejiaSTornerLMJeziorskiMCGonzalezCMoralesMAde la EscaleraGMet alProlactin and 16K prolactin stimulate release of vasopressin by a direct effect on hypothalamo-neurohypophyseal system. Endocrine (2003) 20(1–2):155–62.10.1385/ENDO:20:1-2:155
21
BajouKHerkenneSThijssenVLD’AmicoSNguyenNQBoucheAet alPAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat Med (2014) 20(7):741–7.10.1038/nm.3552
22
ZamoranoMLedesma-ColungaMGAdanNVera-MassieuCLeminiMMendezIet alProlactin-derived vasoinhibins increase anxiety- and depression-related behaviors. Psychoneuroendocrinology (2014) 44:123–32.10.1016/j.psyneuen.2014.03.006
Summary
Keywords
prolactin, vasoinhibins, peripartum cardiomyopathy, prolactin/vasoinhibin axis, bromocriptine, 16 kDa PRL
Citation
Triebel J, Clapp C, Martínez de la Escalera G and Bertsch T (2017) Remarks on the Prolactin Hypothesis of Peripartum Cardiomyopathy. Front. Endocrinol. 8:77. doi: 10.3389/fendo.2017.00077
Received
19 October 2016
Accepted
29 March 2017
Published
11 April 2017
Volume
8 - 2017
Edited by
Ken Ho, Garvan Institute of Medical Research, Australia
Reviewed by
Philippe Chanson, Université Paris-Sud, France; Gudmundur Johannsson, University of Gothenburg, Sweden; Mark Molitch, University of Northwestern – St. Paul, USA
Updates
Copyright
© 2017 Triebel, Clapp, Martínez de la Escalera and Bertsch.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jakob Triebel, jakob.triebel@gmx.de
Specialty section: This article was submitted to Pituitary Endocrinology, a section of the journal Frontiers in Endocrinology
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