Bortezomib Suppresses Abnormal Proliferation, Migration, and Phenotypic Switching of Aortic Smooth Muscle Cells.

BACKGROUND

Atherosclerosis is the leading cause of cardiovascular disease and mortality worldwide. The proliferation, migration, and phenotypic switching of vascular smooth muscle cells are central to its pathogenesis. Bortezomib, the first Food and Drug Administration-approved proteasome inhibitor for multiple myeloma, suppresses the proliferation and migration of pulmonary artery smooth muscle cells. However, its effects on aortic vascular smooth muscle cells (AoSMCs) remain unclear.

METHODS

Rat AoSMCs were treated with platelet-derived growth factor-BB (PDGF-BB) or angiotensin II (Ang II), with or without bortezomib. Cytotoxicity, proliferation, and migration were assessed by MTT, wound healing, and Boyden chamber assays. Intracellular and mitochondrial ROS were measured by DCFH-DA and MitoSOX. mRNA and protein levels of bone morphogenetic protein-2 (BMP-2), Runt-related transcription factor 2 (Runx2), α-smooth muscle actin (α-SMA), phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated protein kinase B (Akt) were assessed by RT-qPCR and Western blotting. Calcium deposition was assessed using Alizarin Red S staining.

RESULTS

Bortezomib attenuated PDGF-BB and Ang II-induced proliferation and migration of AoSMCs accompanied by reduced ROS production and decreased phosphorylation of ERK and Akt. Furthermore, bortezomib suppressed PDGF-BB- and Ang II-induced osteogenic markers (BMP-2 and Runx2) and calcium deposition, while restoring the contractile marker α-SMA, which was inhibited by PDGF-BB and Ang II.

CONCLUSIONS

Bortezomib attenuated PDGF-BB- and Ang II-induced proliferation, migration, and phenotypic switching of AoSMCs, potentially through reduced ROS production. Mechanistically, bortezomib inhibited ERK and Akt phosphorylation and restored a contractile phenotype. These findings suggest that proteasome inhibition may offer a novel therapeutic approach to modulate vascular remodeling in atherosclerosis.