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Dopamine D1 receptor activation ameliorates ox-LDL-induced endothelial cell senescence via CREB/Nrf2 pathway
Yiming Zhao1, Yuxia Li2, Hongxia Li1
1Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, 150081, China.
Abstract:
Endothelial cell senescence is involved in endothelial dysfunction and aging-related vascular diseases. The D1-like dopamine receptor (DR1), a number of G-protein-coupled receptors, is currently under consideration as a potential therapeutic target for the prevention of atherosclerosis. However, the role of DR1 in regulating ox-LDL-stimulated endothelial cell senescence remains unknown. Here, we found that the elevated Prx hyperoxidation and reactive oxygen species (ROS) levels in ox-LDL-treated Human umbilical vein endothelial cells (HUVECs) were observed, suppressed by DR1 agonist SKF38393. Increased proportion of senescence-associated β-galactosidase (SA-β-gal) positive staining cells and activated p16/p21/p53 pathway in ox-LDL-treated HUVECs were significantly abolished by DR1 activation. In addition, SKF38393 increased the phosphorylation of cAMP response element-binding protein (CREB) at serine-133, nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and expression of HO-1 in HUVECs. In contrast, adding H-89, a PKA inhibitor, diminished the effects of DR1 activation. Further studies performed with DR1 siRNA confirmed that DR1 was involved in CREB/Nrf2 pathway. Taken together, DR1 activation reduces ROS production and cell senescence by upregulating CREB/Nrf2 antioxidant signaling in ox-LDL-induced endothelial cells. Thus, DR1 could be a potential molecular target to counteract oxidative stress-induced cellular senescence.
Insights
Dopamine receptor 1 (DR1) activation reduces oxidative stress and endothelial cell senescence induced by oxidized LDL. This occurs by enhancing the CREB/Nrf2 antioxidant pathway, suggesting DR1 as a therapeutic target for vascular aging.
Area of Science:
- Cardiovascular Biology
- Cellular Senescence
- Molecular Pharmacology
Background:
- Endothelial cell senescence contributes to vascular dysfunction and aging.
- Oxidized low-density lipoprotein (ox-LDL) induces endothelial cell senescence.
- The D1-like dopamine receptor (DR1) is a potential target for atherosclerosis prevention.
Purpose of the Study:
- To investigate the role of DR1 in ox-LDL-induced endothelial cell senescence.
- To elucidate the molecular mechanisms underlying DR1's effects on endothelial cells.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) were treated with ox-LDL.
- DR1 agonist SKF38393 and PKA inhibitor H-89 were used.
- DR1 siRNA was employed for knockdown studies.
- Assays included ROS measurement, SA-β-gal staining, Western blotting for p16/p21/p53, CREB phosphorylation, Nrf2 nuclear accumulation, and HO-1 expression.
Main Results:
- DR1 activation by SKF38393 suppressed ox-LDL-induced ROS production and hyperoxidation of Prx.
- DR1 activation reduced the proportion of SA-β-gal positive cells and normalized the p16/p21/p53 pathway.
- SKF38393 increased CREB phosphorylation, Nrf2 nuclear accumulation, and HO-1 expression, effects abolished by H-89.
- DR1 knockdown confirmed its involvement in the CREB/Nrf2 pathway.
Conclusions:
- DR1 activation mitigates ROS production and endothelial cell senescence in ox-LDL-treated cells.
- The protective effects are mediated through the upregulation of the CREB/Nrf2 antioxidant signaling pathway.
- DR1 represents a promising molecular target for counteracting oxidative stress-induced cellular senescence and vascular aging.
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