Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Abstract

Objective-Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in 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 macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability. Approach and Results-Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions. opening, which results in K + efflux that maintains a negative membrane potential. Thus, the initial influx of Ca 2+ feeds forward, thereby, preserving the negative V m (membrane voltage) required for sustained Ca 2+ influx. 12 The Ca 2+ influx leads to an increase in cytosolic Ca 2+ concentration, which is necessary for the translocation of nuclear factors to the nucleus and the initiation of new transcription. Conclusions-TheseParticularly, in macrophages, KCa3.1 has been shown to be involved in activation, migration, proliferation, and respiratory bursting, indicating that KCa3.1 suppression might be helpful in some macrophage-related disorders, such as asthma, multiple sclerosis, stroke, and so forth. [13][14][15] Previous evidence has demonstrated a role for KCa3.1 in atherosclerosis. In mouse models, pharmacological inhibition of KCa3.1 by the selective blocker TRAM-34 attenuates atherosclerotic lesion formation and may provide a novel approach for the prevention and treatment of atherosclerosis. 16 However, in advanced atherosclerotic lesions, the role of KCa3.1 in the pathogenesis of plaque instability and its underlying mechanisms are unknown. A recent study reported that IL-4 stimulation increases KCa3.1 current in microglia, 17 which suggests that KCa3.1 may be involved in the polarization of macrophages and atherosclerotic plaque disruption. In this study, we pharmacologic...

Endothelial Functions

“…Stott et al 46 showed that K V 7 channel-mediated relaxations in response to isoproterenol were dependent on exchange protein directly activated by cAMP in mesenteric artery but not in renal artery in rats, indicating that intermediate signaling steps from β-adrenoceptors to K V 7 channels vary depending on vascular beds. Xu et al 47 showed that blocking K Ca 3.1 channels reduced atherosclerotic burden and enhanced plaque stability in a mouse model of atherosclerosis by inhibiting macrophage differentiation toward proinflammatory M1 phenotype. However, nonspecific inhibition of K Ca 3.1 should require caution because it could lead to microvascular endothelial dysfunction by inhibiting EDH-mediated responses.…”

Adipose‐Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization

“…M1 macrophages increase and sustain the ongoing inflammatory response by producing proinflammatory mediators . Persistent induction of M1 macrophages promotes an inflammatory state and causes tissue injury, which are associated with atherosclerosis progression and plaque rupture . In contrast, M2 macrophages have an antiatherogenic effect through inflammation resolution, tissue repair, and efferocytosis .…”

“…19 Persistent induction of M1 macrophages promotes an inflammatory state and causes tissue injury, which are associated with atherosclerosis progression and plaque rupture. 20,21 In contrast, M2 macrophages have an antiatherogenic effect through inflammation resolution, tissue repair, and efferocytosis. 19,22 Overall, macrophage foam cell formation and polarization are both fundamental contributors to the development and progression of atherosclerotic plaques.…”

Exosomal MALAT1 derived from oxidized low-density lipoprotein-treated endothelial cells promotes M2 macrophage polarization

“…In human atherosclerotic plaques, markers for M1 and M2 macrophages are present in the early and advanced stages of plaque development (16,17). Previous studies in hypercholesterolemic mice have demonstrated that M2 macrophages reduce atherosclerosis, whereas suppression of M2 polarization enhances plaque progression (18)(19)(20). Therefore, it may be concluded that macrophage polarization is important for plaque progression in atherosclerosis.…”