ADAMTS7 Promotes Smooth Muscle Foam Cell Expansion in Atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Atherosclerosis
• Vascular Cell Biology

Background:

• Human genetic studies link ADAMTS7 to atherosclerotic cardiovascular disease.
• ADAMTS7 is a proatherogenic secreted protein, but its cell-specific roles are unknown.

Purpose of the Study:

• To elucidate the cell-specific mechanisms of ADAMTS7 in promoting atherosclerosis.
• To identify the vascular cell types expressing ADAMTS7 and its downstream effects.

Main Methods:

• Single-cell RNA sequencing of human carotid atherosclerosis.
• Generation of smooth muscle cell (SMC)- and endothelial cell (EC)-specific Adamts7 conditional knockout and transgenic mice.
• RNA-sequencing of SMCs and subsequent biochemical assays.

Main Results:

• ADAMTS7 is expressed in SMCs, ECs, and fibroblasts in human atherosclerosis.
• SMC- or EC-specific Adamts7 knockout does not reduce atherosclerosis; transgenic induction increases it.
• In SMCs, ADAMTS7 upregulates CD36 and PU.1, enhancing oxidized low-density lipoprotein (oxLDL) uptake and promoting foam cell formation.

Conclusions:

• ADAMTS7 expression in either SMCs or ECs promotes SMC foam cell formation and atherosclerosis.
• ADAMTS7 drives SMC foam cell formation by increasing oxLDL uptake through PU.1 and CD36.
• Targeting ADAMTS7 may offer a therapeutic strategy for atherosclerotic cardiovascular disease.