Role of plasminogen activator inhibitor-1 in the regulation of mitochondrial function in vascular smooth muscle cells
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Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor produced by vascular smooth muscle cells (VSMCs) and other cells, triggers metabolic dysfunction and cell senescence in obesity. Recent studies suggest that PAI-1 exerts deleterious effects on mitochondrial biogenesis. However, little is known about the specific effects of PAI-1 on mitochondrial function. The purpose of this study was to examine the effects of pharmacological and genetic modulation of PAI-1 expression on mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption in VSMCs. Mitochondrial membrane potential ([delta][psi]m) and reactive oxygen species (ROS) generation were assessed in VSMCs treated with and without PAI-039, a well characterized, highly specific, inhibitor of PAI-1. PAI-039 significantly decreased [delta][psi]m compared to vehicle control. [delta][psi]m and superoxide were assessed in intact vessel coronary artery segments of wild-type (WT) and PAI-1-deficient mouse models. [delta][psi]m and superoxide were significantly decreased in vessels from PAI-1-deficient mice compared to WT control. The oxygen consumption rate (OCR) in the PAI-1 deficient cultured aortic smooth muscle cells showed no significant difference in OCR compared to the WT controls (n=4), contrary to our hypothesis. RNA-seq analysis was carried out by using PAI-039 to examine the effects of PAI-1 on the transcriptome of cultured human coronary artery VSMCs. Eleven differentially expressed genes (DEGs) were identified from the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, 9 (82 percent) of which were significantly increased by PAI-039, suggesting an upregulation of AMPK signaling by PAI-039. RNA-seq revealed other relevant changes including upregulation of the longevity pathway and superoxide dismutase-2 (SOD-2), a major regulator of mitochondrial superoxide content. These results show that PAI-1 regulates mitochondrial function in vascular SMCs. They also provide important mechanistic insights into how PAI-1 may regulate the key roles of VSMCs in vascular remodeling, including clinical disorders, such as atherosclerosis and restenosis.
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M.S.