A Novel FNDC1-NAMPT-NAD axis is Implicated in Small and Large-vessel Arterial Disease and Drives Vascular...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Biochemistry

Background:

• Vascular calcification is a common feature in cardiovascular diseases, but its underlying molecular mechanisms are not fully understood.
• Identifying novel regulators is crucial for developing effective treatments.

Purpose of the Study:

• To identify and characterize novel molecular regulators of vascular calcification.
• To investigate the role of fibronectin type III domain-containing 1 (FNDC1) in vascular calcification.
• To explore the therapeutic potential of targeting the FNDC1 pathway.

Main Methods:

• Integrative transcriptomic profiling of human calciphylaxis and atherosclerotic lesions.
• In vitro studies using primary human vascular smooth muscle cells.
• Murine models of vascular calcification.
• Analysis of UK Biobank data (42,687 participants).

Main Results:

• FNDC1 was significantly upregulated in human vascular calcification lesions.
• FNDC1 promoted osteogenic phenotype and vascular calcification via PI3K/AKT signaling and metabolic reprogramming.
• FNDC1 directly interacts with NAMPT, increasing intracellular NAD+ levels.
• Genetic deletion of FNDC1 or NAMPT inhibition reduced arterial calcification in mice.
• Elevated circulating FNDC1 levels predicted cardiovascular risk in a large human cohort.

Conclusions:

• FNDC1 is a key mediator of vascular calcification across different vascular beds.
• The FNDC1-NAMPT-NAD+ axis represents a novel therapeutic target for vascular calcification and related cardiovascular diseases.