ADAMTS7 promotes smooth muscle foam cell expansion in atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genetics

Background:

• Human genetic studies link ADAMTS7 to atherosclerotic cardiovascular disease.
• ADAMTS7 is proatherogenic and induced by vascular injury in mice.
• Cell-specific mechanisms of ADAMTS7 proatherogenicity are unclear.

Purpose of the Study:

• Identify vascular cell types expressing ADAMTS7.
• Determine the role of ADAMTS7 in atherosclerosis.
• Elucidate the molecular mechanisms of ADAMTS7-driven atherosclerosis.

Main Methods:

• Single-cell RNA sequencing of human carotid atherosclerosis.
• SMC- and EC-specific Adamts7 conditional knockout and transgenic mice.
• RNA-sequencing, ATAC-seq, and motif analysis in SMCs.

Main Results:

• ADAMTS7 is expressed in human vascular SMCs, ECs, and fibroblasts.
• SMC- or EC-specific Adamts7 knockout did not reduce atherosclerosis.
• Transgenic induction of Adamts7 in SMCs or ECs increased atherosclerosis.
• ADAMTS7 promotes SMC foam cell formation and decreases fibrous cap formation.
• ADAMTS7 upregulates SMC lipid uptake via CD36, driven by an AP-1/PU.1 axis.

Conclusions:

• ADAMTS7 promotes atherosclerosis by driving SMC foam cell formation.
• The AP-1/PU.1/CD36 regulatory axis is a key mechanism.
• Targeting this pathway may offer novel therapeutic strategies for cardiovascular disease.