Abstract
The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO2) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO2 levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO2 supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO2/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO2/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO2/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.
Highlights
The proliferation and migration of vascular smooth muscle cells are the pathophysiological basis of many cardiovascular diseases
There was no significant difference in the primary vascular smooth muscle cell (VSMC) expression of aspartate aminotransferase (AAT) between the control VSMCs and VSMCs treated with different concentrations of ET-1 (10-8, 10-7, or 10-6 M)
We found that ET-1 reduced SO2 generation by decreasing the activity of AAT without influencing aspartate aminotransferase 1 (AAT1) and aspartate aminotransferase 2 (AAT2) expression and that the ET-1-mediated reduction in the SO2 level participated in the excessive proliferation and migration of VSMCs (Figure 4)
Summary
The proliferation and migration of vascular smooth muscle cells are the pathophysiological basis of many cardiovascular diseases. The impacts of small vasoactive molecules on vascular proliferation, migration, and remodeling depend on the integrated effects of the molecules [1, 2]. It is of great scientific significance to explore the interactions between gasotransmitters and vasoactive peptides and the regulatory mechanisms for vasoactive molecules to understand the possible mechanism underlying vascular smooth muscle cell (VSMC) proliferation and migration. Endothelin-1 (ET-1) is a plasma protein secreted by vascular endothelial cells that possesses potent vasoconstrictive activity [3]. It induces biological or pathological effects upon binding to the ETA receptor in VSMCs [4].
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