Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

Setareh Orth-Alampour (1) , Nathalie Gayrard (2, 3) , Silvia Salem (4) , Shruti Bhargava (1) , Vera Jankowski (1) , Bernard Jover (5) , Cécile Notarnicola (5) , Heidi Noels (1) , Emiel van Der Vorst (1) , Christoph Kuppe (1) , Michael Wolf (1) , Claudia Goettsch (1) , Wendy Theelen (1) , Heike Bruck (6, 7) , Danilo Fliser (8) , Joseph Loscalzo (9) , Zhuojun Wu (1) , Nikolaus Marx (1) , Walter Zidek (10) , Àngel Argilés (2, 3) , Joachim Jankowski (1, 11)

1 RWTH - Rheinisch-Westfälische Technische Hochschule Aachen University
2 R&D - RD-Néphrologie
3 BC2M - Biocommunication en Cardio-Métabolique
4 MHH - Medizinische Hochschule Hannover = Hannover Medical School
5 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
6 AöR - University Hospital Essen
7 Klinikum Krefeld
8 Universitätsklinikum des Saarlandes
9 HMS - Harvard Medical School [Boston]
10 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
11 Maastricht University [Maastricht]

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-κB 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.

Mots clés: Vascular calcifcation; Adrenal glands; Vascular smooth muscle cell transdiferentiation; Cardiorenal syndrome

Domaines: Biochimie, Biologie Moléculaire; Cardiologie et système cardiovasculaire

Setareh Orth-Alampour, Nathalie Gayrard, Silvia Salem, Shruti Bhargava, Vera Jankowski, et al.. Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation. Basic Research in Cardiology, 2021, 116 (1), pp.57. ⟨10.1007/s00395-021-00899-z⟩. ⟨hal-03380227v2⟩