Effects of rosuvastatin on the production and activation of matrix metalloproteinase-2 and migration of cultured rat vascular smooth muscle cells induced by homocysteine

Abstract

Abstract:Objective: To test the influence of homocysteine on the production and activation of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) and on cell migration of cultured rat vascular smooth muscle cells (VSMCs). Also, to explore whether rosuvastatin can alter the abnormal secretion and activation of MMP-2 and TIMP-2 and migration of VSMCs induced by homocysteine. Methods: Rat VSMCs were incubated with different concentrations of homocysteine (50-5 000 μmol/L). Western blotting and gelatin zymography were used to investigate the expressions and activities of MMP-2 and TIMP-2 in VSMCs in culture medium when induced with homocysteine for 24, 48, and 72 h. Transwell chambers were employed to test the migratory ability of VSMCs when incubated with homocysteine for 48 h. Different concentrations of rosuvastatin (10 −9 -10 −5 mol/L) were added when VSMCs were induced with 1 000 μmol/L homocysteine. The expressions and activities of MMP-2 and TIMP-2 were examined after incubating for 24, 48, and 72 h, and the migration of VSMCs was also examined after incubating for 48 h. Results: Homocysteine (50-1 000 μmol/L) increased the production and activation of MMP-2 and expression of TIMP-2 in a dose-dependent manner. However, when incubated with 5 000 μmol/L homocysteine, the expression of MMP-2 was up-regulated, but its activity was down-regulated. Increased homocysteine-induced production and activation of MMP-2 were reduced by rosuvastatin in a dose-dependent manner whereas secretion of TIMP-2 was not significantly altered by rosuvastatin. Homocysteine (50-5 000 μmol/L) stimulated the migration of VSMCs in a dose-dependent manner, but this effect was eliminated by rosuvastatin. Conclusions: Homocysteine (50-1 000 μmol/L) significantly increased the production and activation of MMP-2, the expression of TIMP-2, and the migration of VSMCs in a dose-dependent manner. Additional extracellular rosuvastatin can decrease the excessive expression and activation of MMP-2 and abnormal migration of VSMCs induced by homocysteine.

Atorvastatin attenuates homocysteine‐induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK

“…In the present study, it was found that Hcy (50–500 μmol/L for 6–24 h) induced VSMCs migration in a time and dose dependent manner. The results were consistent with data published previously . This study also showed that ROS are strongly involved in Hcy induced VSMCs migration, since radical scavengers NAC reduced VSMCs migration by 17.97%.…”

Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

“…Derangement of MMP-2 expression and activity alters the balance between ECM synthesis and degradation, resulting in excessive collagen deposition and reduced structural integrity in the myocardium. Increasing degradation of ECM supplies space for the proliferation and migration of HCF and other macrophagocytes, which secrete inflammatory and growth factors, further enhancing the cardiac remodeling process (21). Siddesha et al (22), showed that sustained induction and activation of MMPs and the destruction and deposition of ECM can result in cardiac fibrosis.…”

Polyphenols and Polypeptides in Chinese Rice Wine Inhibit Homocysteine-induced Proliferation and Migration of Vascular Smooth Muscle Cells

“…18 MMPs and TIMPs together maintain the balance of ECM and participate in the regulation of VSMC migration and proliferation. 13 Oak et al 19 found that red wine polyphenols inhibited VSMC proliferation and migration mainly by decreasing the expression and activity of MMP-2. Recent studies further confirmed that resveratrol from red wine polyphenols could inhibit VSMC proliferation by suppressing ROS generation and inhibit VSMC migration by reducing MMPs expression.…”

“…The activated MMP-2 can also activate other signaling pathways such as p-AKT and p-ERK1/2 that could induce the migration and proliferation of VSMCs, 24,29,30 and the degradation of ECM supplies space for the migration and proliferation of VSMCs. 13 What is more, the activated VSMCs can then secrete and activate more MMP-2 and aggravate the imbalance of MMP-2/TIMP-2, resulting in the development and rupture of atherosclerotic plaques. 31 Our results showed that polyphenols and polypeptides in the Chinese rice wine could decrease the expression and activity of MMP-2 and MMP-9.…”

“…11,12 Our previous research has already proved that VSMCs can abnormally secret and activate matrix metalloproteinases (MMPs, especially MMP-2/9) and TIMPs (especially TIMP-2) when activated by Hcy. 13 Thus, in this experiment, we used Hcy to induce the proliferation and migration of VSMCs and identified the exact ingredients in Chinese rice wine that could inhibit the proliferation and migration of VSMCs.…”