Matrix Metalloproteases and Cathepsin D in Human Serum do not Cleave Prolactin to Generate Vasoinhibin

Triebel, Jakob; Schauer, Nicole; Zamora, Magdalena; Moreno-Vega, Aura Ileana; Escalera, Gonzálo Martínez de la; Clapp, Carmen; Bertsch, Thomas

doi:10.7754/clin.lab.2019.191017

Cited by 4 publications

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“…Along this line, it can be speculated that PL-derived vasoinhibin from the placenta can enter the maternal circulation and contribute to endothelial dysfunction and the development of hypertension, as seen in PE. Vasoinhibin generation by cleavage of PL in the circulation may also occur but is rather unlikely [ 21 ]. Testing these hypotheses should include a quantitative evaluation of placental and circulating PL-derived vasoinhibin in a case-control study, as well as functional assays of the placental vasoinhibin, the evaluation of enzymes responsible for its generation, and the analysis of PL mutations at vasoinhibin-generating cleavage sites [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Human Placental Tissue Contains A Placental Lactogen–Derived Vasoinhibin

Markl-Hahn

Neugebauer

Lenke

et al. 2022

Journal of the Endocrine Society

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Hormonal factors impacting the vascular adaptions of the uteroplacental unit in non-complicated and complicated pregnancies are of interest. Here, 4 human placentas from women with and without preeclampsia were investigated for the presence of placental lactogen derived, antiangiogenic vasoinhibin. Western blotting and mass spectrometry of placental tissue revealed the presence of a 9 kDa placental lactogen derived vasoinhibin, the normal 22 kDa full-length placental lactogen, and a 28 kDa immunoreactive protein of undetermined nature. The sequence of the 9 kDa vasoinhibin includes the antiangiogenic determinant of vasoinhibin and could constitute a relevant factor in normal pregnancy and preeclampsia.

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Section: Discussionmentioning

confidence: 99%

Human Placental Tissue Contains A Placental Lactogen–Derived Vasoinhibin

Markl-Hahn

Neugebauer

Lenke

et al. 2022

Journal of the Endocrine Society

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“…measured in some of the samples that indicates levels in the µg-range, however, appears too high given the low-ng range for PRL, and is therefore awaiting evaluation during further serum ELISA development. For example, PRL-immunoreactive proteins in the serum, which appear not to be 23 kDa PRL, such as the high abundant 28 kDa protein in human sera, which may indicate a vasoinhibin dimer ( 26 , 27 ), should be identified and tested for their affinity with the vasoinhibin-specific monoclonal antibodies. Also, the issue of immunoglobulin cross-reactivity with anti-PRL antisera ( 28 ) requires attention, and an interference between the vasoinhibin-specific monoclonal antibodies and immunoglobulins should be excluded.…”

Section: Discussionmentioning

confidence: 99%

Development of Vasoinhibin-Specific Monoclonal Antibodies

et al. 2021

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Vasoinhibin is a protein hormone with antiangiogenic, antivasodilatatory, and antivasopermeability effects generated by the proteolytic cleavage of prolactin. The discovery of its role in diabetic retinopathy and peripartum cardiomyopathy led to the evaluation of new pharmacological treatments in clinical interventional trials. However, the quantitative evaluation of vasoinhibin in biological samples from patients has not been possible due to the lack of vasoinhibin-specific antibodies. Recently, loop 1 of vasoinhibin was identified to have a different three-dimensional structure compared to PRL, and thus to contain vasoinhibin-specific epitopes. Here, we report the development of two sets of vasoinhibin-specific monoclonal antibodies against two neighboring regions of the vasoinhibin loop 1. An experimental sandwich ELISA with two monoclonal anti-vasoinhibin antibodies was developed, which had no cross-reactivity to recombinant human full-length prolactin. The ELISA had a quantitation limit of 100 ng/ml, and intra-assay- and inter-assay coefficients of variation of 12.5% and 14%, respectively. The evaluation of 15 human serum samples demonstrated concentrations of below limit of detection (n=3), below limit of quantitation (n=1) and between 0.23 µg/ml (230 ng/ml) to 605 µg/ml (n=12) in the quantifiable range. Despite the high specificity of the monoclonal-monoclonal antibody sandwiches which discriminate vasoinhibin from PRL, there might be cross-reactivities by serum proteins other than vasoinhibin. A fully established vasoinhibin ELISA may support diagnostic and therapeutic measures in vascular diseases.

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“…were shown to be elevated in PPCM, the role of 16 kDa prolactin remains a topic of debate since cathepsin D produces five distinct vasoinhibins of which four are potent antiangiogenic agents and should be investigated further 147,160 . Moreover, human prolactin is not readily cleaved by cathepsin D in most extracellular conditions, mostly dependent on pH 161,162 .…”

Section: Translating Pathophysiology From Mice To Humansmentioning

confidence: 99%

Pathophysiology and risk factors of peripartum cardiomyopathy

et al. 2022

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Peripartum cardiomyopathy (PPCM) is a potentially fatal form of idiopathic heart failure with varying incidences among countries and races. The cause of PPCM is uncertain but it may result from a combination of environmental and genetic factors, as well as pregnancy associated conditions such as pre-eclampsia. Animal studies suggested that impaired vascular and metabolic function may be central to the development of PPCM. Clarifying the pathogenic mechanisms is necessary to establish new therapies to improve the outcomes of patients with PPCM. Pregnancy hormones tightly coordinate a plethora of maternal adaptive responses, including haemodynamic, vascular, structural, and metabolic changes of the cardiovascular system. While pregnancy is considered to be a cardiovascular challenge, hormonal effects uniquely drive systemic insulin resistance and mostly fatty acid-dependent cardiac metabolism. In PPCM, the peripartum period is associated with profound and rapid hormonal changes that result in a brief period of disrupted cardiovascular (metabolic) homeostasis prone to secondary perturbations. This review summarizes and reflects on recent literature on the potential pathophysiological mechanisms and risk factors for PPCM with a focus on the maternal cardiovascular changes associated with pregnancy. We provide an updated framework to improve understanding of PPCM pathogenesis, which may lead to a better disease definition.

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Matrix Metalloproteases and Cathepsin D in Human Serum do not Cleave Prolactin to Generate Vasoinhibin

Cited by 4 publications

References 0 publications

Human Placental Tissue Contains A Placental Lactogen–Derived Vasoinhibin

Human Placental Tissue Contains A Placental Lactogen–Derived Vasoinhibin

Development of Vasoinhibin-Specific Monoclonal Antibodies

Pathophysiology and risk factors of peripartum cardiomyopathy

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