Yuan-Yuan Wang1, Hui Li2, Xing-Hua Wang1, Meng Yuan1, Guang-Ping Li3. 1. Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Department of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China. 2. Department of Endocrinology and Metabolism, General Hospital of Tianjin Medical University, Tianjin 300052, People's Republic of China. 3. Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Department of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China. Electronic address: tjcardiol@126.com.
Abstract
OBJECTIVE: This study investigated the molecular mechanisms underlying the inhibition of MMP-9 expression by probucol, which is widely used for atherosclerotic prevention, in cultured human umbilical vein endothelial cells (HUVECs) and apoE knockout mice. MATERIALS AND METHODS: We used three target scan algorithms and observed that microRNA (miR)-497 targeted MEK1, a member of the MAPK/ERK signaling involved in regulating MMP-9 expression. HUVECs were treated with TNFα, and apoE knockout mice were fed a high-fat/high-cholesterol diet with or without probucol pretreatment. We focused on the association between miR-497 and MAPK/ERK signaling and MMP-9 expression. RESULTS: First, miR-497 expression was significantly higher in the probucol-treated HUVECs and apoE knockout mice compared with non-probucol-treated HUVECs and apoE knockout mice (both p<0.05). Second, MAPK/ERK signaling and MMP-9 levels were downregulated in probucol-treated HUVECs that were treated with TNFα (p<0.01), while MAPK/ERK signaling and MMP-9 levels were upregulated after suppression of miR-497 (p<0.01). Third, probucol increased miR-497 expression levels in the aortas of apoE knockout mice (p<0.05) while decreasing the levels of serum lipids and plaque areas (p<0.05), which decreased the MAPK/ERK signaling and MMP-9 levels (p<0.05). CONCLUSIONS: Probucol inhibits MMP-9 expression through regulating miR-497 in HUVECs and apoE knockout mice.
OBJECTIVE: This study investigated the molecular mechanisms underlying the inhibition of MMP-9 expression by probucol, which is widely used for atherosclerotic prevention, in cultured human umbilical vein endothelial cells (HUVECs) and apoE knockout mice. MATERIALS AND METHODS: We used three target scan algorithms and observed that microRNA (miR)-497 targeted MEK1, a member of the MAPK/ERK signaling involved in regulating MMP-9 expression. HUVECs were treated with TNFα, and apoE knockout mice were fed a high-fat/high-cholesterol diet with or without probucol pretreatment. We focused on the association between miR-497 and MAPK/ERK signaling and MMP-9 expression. RESULTS: First, miR-497 expression was significantly higher in the probucol-treated HUVECs and apoE knockout mice compared with non-probucol-treated HUVECs and apoE knockout mice (both p<0.05). Second, MAPK/ERK signaling and MMP-9 levels were downregulated in probucol-treated HUVECs that were treated with TNFα (p<0.01), while MAPK/ERK signaling and MMP-9 levels were upregulated after suppression of miR-497 (p<0.01). Third, probucol increased miR-497 expression levels in the aortas of apoE knockout mice (p<0.05) while decreasing the levels of serum lipids and plaque areas (p<0.05), which decreased the MAPK/ERK signaling and MMP-9 levels (p<0.05). CONCLUSIONS:Probucol inhibits MMP-9 expression through regulating miR-497 in HUVECs and apoE knockout mice.