TY - JOUR
T1 - Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation
AU - Orth-Alampour, S.
AU - Gayrard, N.
AU - Salem, S.
AU - Bhargava, S.
AU - Jankowski, V.
AU - Jover, B.
AU - Notarnicola, C.
AU - Noels, H.
AU - van der Vorst, E.P.C.
AU - Kuppe, C.
AU - Wolf, M.
AU - Goettsch, C.
AU - Theelen, W.
AU - Bruck, H.
AU - Fliser, D.
AU - Loscalzo, J.
AU - Wu, Z.J.
AU - Marx, N.
AU - Zidek, W.
AU - Argiles, A.
AU - Jankowski, J.
N1 - Funding Information:
Open Access funding enabled and organized by Projekt DEAL. This study was supported by a grant from the German Research Foundation (DFG, SFB/TRR219 project C-04 and S-03 to J.J, V.J., and S.OA and to D.F (C-08) and HN and NM (M-05).) (Project-ID 322900939).
Funding Information:
The authors were supported by grants from Deutsche Forschungsgemeinschaft (DFG) (SFB TRR 219; C-04, S-03, M-05; Project-ID: 322900939), the Federal Ministry of Education and Research (MIVAKA) (LS-2-1-001), and the European Union EU-ITN-H2020 to “INTRICARE” (722609) and “CaReSyAn” (764474).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the "calcification blocking factor" (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-kappa B activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.
AB - The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the "calcification blocking factor" (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-kappa B activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.
KW - Vascular calcification
KW - Adrenal glands
KW - Vascular smooth muscle cell transdifferentiation
KW - Cardiorenal syndrome
KW - PHOSPHATE-INDUCED CALCIFICATION
KW - SMOOTH-MUSCLE-CELLS
KW - ARTERIAL STIFFNESS
KW - OSTEOBLASTIC DIFFERENTIATION
KW - CALCIUM DEPOSITION
KW - SECRETORY VESICLES
KW - RAT MODEL
KW - IN-VITRO
KW - EXPRESSION
KW - VIVO
U2 - 10.1007/s00395-021-00899-z
DO - 10.1007/s00395-021-00899-z
M3 - Article
C2 - 34647168
SN - 0300-8428
VL - 116
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 1
M1 - 57
ER -