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. Author manuscript; available in PMC: 2022 Sep 14.
Published in final edited form as: J Am Coll Cardiol. 2021 Sep 14;78(11):1145–1165. doi: 10.1016/j.jacc.2021.06.049

Figure 1. Mechanisms Contributing to MAC Pathogenesis.

Figure 1.

(1) Extracellular matrix (ECM) cues are detected via DDR1 receptor promoting the activation of osteogenic genes. (2) DNA damage response pathway leads to the accumulation of poly (AMP) ribose (PAR) molecules. PAR are secreted in matrix vesicles (MVs) and act as niduses for calcification. (3) Calcium/phosphate minerals can nucleate in the ECM, but this is inhibited via MGLA. PiT1/2 transporter removes inorganic phosphate (Pi) from the extracellular environment. (4) TNAP converts the endogenous inhibitor of mineral nucleation, pyrophosphate (PPi), into the mineral building block, Pi. (5) PPi and AMP are produced from the activity of ENPP1 in the extracellular ATP metabolic pathway. The substrate for ABCC6 is thought to also be ATP but currently not known. (6) CD73-mediated A2b adenosine receptor signaling functions to suppress MAC via cAMP-mediated repression of FOXO1 gene. With a lack of this signaling FOXO1 upregulates ALPL/TNAP. Created