Abstract
Background Emerging evidence indicates that pro-inflammatory monocyte-macrophage polarization imbalance play key role in the atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in transcriptional regulation of monocyte-macrophage polarization and its relation to plaque instability is still unknown. Methods THP-1 monocytes were differentiated into macrophages using phorbol myristate acetate (PMA) and polarized into M1 by IFN-γ and LPS and into M2 macrophages by IL-4. Monocytes/macrophages were treated with KCa3.1 blocker TRAM-34 during differentiation or polarization. Animal model of plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. From 6 weeks after surgery, the animals were treated with subcutaneous injection of TRAM-34 (120 mg/kg/d), or vehicle (miglyol 812) for 4 weeks. Phenotypic markers of macrophages and histological plaque characteristics were analysed. Results Significant up-regulation of KCa3.1 expression was found during the differentiation of THP-1 monocytes to macrophages. TRAM-34 treatment reduced the polarization of THP-1-derived macrophages to proinflammatory M1 macrophage while increasing the polarization of THP-1-derived macrophages to anti-inflammatory M2 macrophages. Further mechanistic studies indicated that KCa3.1 blocker promoted an M2 macrophage phenotype through up-regulation the activation of PPAR-γ. In animal models, KCa3.1 blockade therapy with TRAM-34 strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries. Moreover, macrophages within atherosclerotic lesions of mice receiving TRAM-34 injection showed decreased expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Conclusion These results suggest that blockade of KCa3.1 suppresses plaque instability at the advanced stage of atherosclerosis by promoting polarization of macrophages toward an M2 phenotype.
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