Inhibition of mitochondrial complex I activity attenuates neointimal hyperplasia by inhibiting smooth muscle cell proliferation and migration.

Enhanced mitochondrial respiration in vascular smooth muscle cells (VSMCs) is involved in neointima formation in response to vascular injury. In the present study, we investigated the effect of rotenone (ROT), a mitochondrial respiratory chain complex I inhibitor, on VSMC proliferation and migration in vitro, and on femoral artery neointimal hyperplasia induced by wire injury. ROT treatment remarkably ameliorated neointima formation after vascular injury in line with the reduced collagen deposition and significantly restored α-smooth muscle actin (SMA) expression in the neointima. In vitro, ROT markedly suppressed platelet-derived growth factor (PDGF)-BB-induced mouse aorta smooth muscle (MOVA) cell proliferation, migration, and adenosine triphosphate (ATP) production, while the cell viability of MOVA cells was not affected by ROT at concentrations of 10-100 nM. Meanwhile, ROT blocked PDGF-BB-induced cell cycle progression by arresting cell cycle in G0/G1 phase. Interestingly, ROT inhibited the phosphorylation of protein kinase B (AKT), but not extracellular signal-regulated kinase (ERK) 1/2, in response to PDGF-BB, accompanied with the blockade of matrix metalloproteinase-9 (MMP-9) upregulation and reactive oxygen species (ROS) production. These findings indicated that ROT could block neointima formation by preventing the proliferation and migration of MOVA cells, possibly by inhibiting the mitochondrial respiratory chain activity, ATP production, AKT phosphorylation, MMP-9 activation, and ROS production. Thus, inhibiting mitochondrial respiratory chain activity might represent a new strategy to treat neointima formation-associated vascular diseases.