Min Qiu1, Junbing Ma2, Juan Zhang2, Xiaohua Guo2, Quanli Liu3, Zheng Yang4. 1. Second Department of Cardiovascular Diseases, First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, 014010, China; Department of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, 014060, China. 2. Second Department of Cardiovascular Diseases, First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, 014010, China. 3. Department of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, 014060, China. 4. Second Department of Cardiovascular Diseases, First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, 014010, China. Electronic address: zheng_yang_bt@126.com.
Abstract
BACKGROUND: The infiltration and activation of macrophages play key roles in arterial restenosis, providing a promising strategy for the treatment of restenosis caused by intimal hyperplasia. Although miR-150 has been implicated in cardiovascular diseases, the individual effect of miR-150 on intimal hyperplasia remains unclear. METHODS AND RESULTS: We observed that the expression of miR-150 was robustly reduced in proinflammatory M1 macrophages and reversely induced in resolving M2 macrophages. An in vitro experiment demonstrated that miR-150 deficiency promoted extensive upregulation of the expression of M1 markers but attenuated the expression of M2 macrophage markers. MiR-150 enhanced the proliferation and migration of vascular smooth muscle cells (VSMCs) when co-cultured with conditioned medium from polarized macrophages upon LPS or IL-4 stimulation. Mechanistically, the bioinformatics analysis and luciferase assay results showed that miR-150 directly targeted STAT1 and STAT1 was required for the effect of miR-150 knockout on macrophage polarization. More importantly, we showed that knockout of miR-150 accelerated neointima formation, accompanied by the activation of M1 macrophages and the inactivation of M2 macrophages. Furthermore, miR-150 deficiency in marrow-derived cell accelerated neointima formation. CONCLUSION: Our research demonstrated that miR-150 deficiency promoted intimal hyperplasia with high ratios of M1 to M2 macrophages and subsequently increased VSMCs proliferation and migration, which were partially mediated by directly targeting to STAT1. Collectively, these results suggested that miR-150 may act as a novel therapeutic target for arterial restenosis.
BACKGROUND: The infiltration and activation of macrophages play key roles in arterial restenosis, providing a promising strategy for the treatment of restenosis caused by intimal hyperplasia. Although miR-150 has been implicated in cardiovascular diseases, the individual effect of miR-150 on intimal hyperplasia remains unclear. METHODS AND RESULTS: We observed that the expression of miR-150 was robustly reduced in proinflammatory M1 macrophages and reversely induced in resolving M2 macrophages. An in vitro experiment demonstrated that miR-150 deficiency promoted extensive upregulation of the expression of M1 markers but attenuated the expression of M2 macrophage markers. MiR-150 enhanced the proliferation and migration of vascular smooth muscle cells (VSMCs) when co-cultured with conditioned medium from polarized macrophages upon LPS or IL-4 stimulation. Mechanistically, the bioinformatics analysis and luciferase assay results showed that miR-150 directly targeted STAT1 and STAT1 was required for the effect of miR-150 knockout on macrophage polarization. More importantly, we showed that knockout of miR-150 accelerated neointima formation, accompanied by the activation of M1 macrophages and the inactivation of M2 macrophages. Furthermore, miR-150 deficiency in marrow-derived cell accelerated neointima formation. CONCLUSION: Our research demonstrated that miR-150 deficiency promoted intimal hyperplasia with high ratios of M1 to M2 macrophages and subsequently increased VSMCs proliferation and migration, which were partially mediated by directly targeting to STAT1. Collectively, these results suggested that miR-150 may act as a novel therapeutic target for arterial restenosis.