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Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases
Freise, Christian ;  Kretzschmar, Nadja ;  Querfeld, Uwe

HaupttitelWnt signaling contributes to vascular calcification by induction of matrix metalloproteinases
AutorFreise, Christian
AutorKretzschmar, Nadja
AutorQuerfeld, Uwe
Seitenzahl8 S.
Freie SchlagwörterMatrix metalloproteinases; Vascular calcification; Chronic kidney disease; Vascular smooth muscle cells; Wnt pathway; MOVAS-1
DDC610 Medizin und Gesundheit
Auch erschienen inBMC Cardiovascular Disorders. - 16 (2016), Artikel Nr. 185
ZusammenfassungBackground

Vascular calcifications such as arteriosclerosis, which is characterized by a calcificiation of the tunica media, represent major comorbidities e.g. in patients with chronic kidney disease (CKD). An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMC) resembling osteogenesis. The matrix metalloproteinases (MMP)-2 and −9 were shown to promote these VSMC calcifications and their inhibition is of therapeutic value to prevent arteriosclerosis in preclinical studies. Aiming for an understanding of the underlying regulatory mechanisms of MMPs we here investigated, if the MMP-mediated VSMC calcification involves altered signaling of the Wnt pathway, which is known to impact osteogenesis.

Methods

We used an experimental in vitro model of vascular calcification. Transdifferentiation/calcification of murine VSMC was induced by elevated calcium and phosphorus levels. Calcification was assessed by calcium and alkaline phosphatase measurements. Activation/activity of the gelatinases MMP-2 and MMP-9 was assessed by conversion of fluorescence-labelled substrates. Activation of the Wnt pathway was analysed by a reporter gene assay.

Results

Besides pro-calcifying culture conditions, also activation of Wnt signaling by a specific agonist (under normal culture conditions) stimulated VSMC-calcification accompanied by enhanced expression and secretion of the gelatinases MMP-2 and −9. Vice versa, recombinant MMP-2 and −9 induced a time-delayed activation of Wnt signaling after 72 h in VSMC but showed no direct effects after 24–48 h. These effects were blocked by pharmacological inhibition of MMPs or of Wnt signaling.

Conclusions

Our study suggests that the pro-calcifying environment in CKD induces Wnt signaling in VSMC which in turn contributes to the induction of MMPs which then foster the development of arteriosclerosis. Thus, besides MMP inhibition, the inhibition of Wnt signaling in VSMC might represent a therapeutic target for the prevention of vascular calcifications.
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Fachbereich/EinrichtungMedizinische Fakultät Charité - Universitätsmedizin Berlin
Erscheinungsjahr2016
Dokumententyp/-SammlungenWissenschaftlicher Artikel
SpracheEnglisch
RechteCreative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Anmerkungen des AutorsDer Artikel wurde in einer reinen Open-Accessö-Zeitschrift publiziert.
Erstellt am17.11.2016 - 11:49:33
Letzte Änderung17.11.2016 - 11:57:32
 
Statische URLhttp://edocs.fu-berlin.de/docs/receive/FUDOCS_document_000000025719
DOI10.1186/s12872-016-0362
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