Identification and characterization of a novel vascular calcification mediator

Shruti Bhargava (Aachen)1, E. Merckelbach (Aachen)1, Z. Wu (Aachen)1, V. Jankowski (Aachen)1, J. Jankowski (Aachen)1

1Uniklinik RWTH Aachen Institut für Molekulare Herz-Kreislaufforschung (IMCAR) Aachen, Deutschland


Background: Patients undergoing dialysis for chronic kidney disease (CKD) often suffer from cardiovascular complications such as vascular calcification. In this study, a recently identified endogenous peptide was systematically explored elucidating its regulatory role in the processes of vascular calcification. Our discoveries unveil a previously unexplored cardioprotective function of the adrenal glands, particularly effective against vascular calcification associated CKD.

Methods: To identify potential mediators, mass spectrometric analysis was conducted, and the results were compared with relevant databases. Chromatographic fractions derived from bovine adrenal glands were tested for their effect on vascular calcification processes using in vitro, ex vivo, and in vivo rat model of elastocalcinosis.

Results: A 19-aa peptide was identified, and its levels were quantified in the serum of end-stage renal disease patients undergoing dialysis, as well as in matched controls. This newly identified peptide, named Calcification Blocking Factor (CBF), demonstrated significant protective effects against vascular calcification. Treatment with CBF effectively reduced the calcium content in cells, thoracic aortic rings cultured under calcifying conditions, and aortas from elastocalcinosis animal models. CBF exerts its protective effects by inhibiting the transdifferentiation of aortic smooth muscle cells into osteoblast-like cells, which are responsible for driving the progression of vascular calcification. CBF interacts with the sodium-dependent phosphate transporter PIT-1 and hinders NF-κB activation and the BMP2/p-SMAD pathway, all implicated in vascular calcification. CBF treatment reduced arterial stiffness in elastocalcinosis animals. CKD patients, susceptible to vascular calcification, showed decreased CBF concentration in serum.The 19-amino acid peptide is derived from the enzymatic cleavage of the adrenal protein chromograninA by calpain1 and kallikrein. Further analysis revealed that a specific 6-8 amino acid sequence within the 19-amino acid peptide serves as the active site responsible for the calcification-blocking properties of CBF.

Conclusion: Our findings suggest that CBF, a novel inhibitor of vascular calcification derived from the adrenal glands inhibits vascular calcification by inhibiting smooth muscle cells transdifferentiation.
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