Abstract
The formation of foam cells, which are macrophages that have engulfed oxidized low-density lipoprotein (OxLDL), constitutes the first stage in the development of atherosclerosis. Previously, we found that knocking down galectin-12, a negative regulator of lipolysis, leads to reduced secretion of monocyte chemoattractant protein-1 (MCP-1), a chemokine that plays an important role in atherosclerosis. This prompted us to study the role of galectin-12 in atherosclerosis. With that aim, we examined foam cell formation in Gal12‒/‒ murine macrophages exposed to OxLDL and acetylated LDL (AcLDL). Then, we generated an LDL receptor and galectin-12 double knockout (DKO) mice and studied the effect of galectin-12 on macrophage function and atherosclerosis. Lastly, we evaluated the role of galectin-12 in human THP-1 macrophages using a doxycycline-inducible conditional knockdown system. Galectin-12 knockout significantly inhibited foam cell formation in murine macrophages through the downregulation of cluster of differentiation 36 (CD36), and the upregulation of ATP Binding Cassette Subfamily A Member 1 (ABCA1), ATP Binding Cassette Subfamily G Member 1 (ABCG1), and scavenger receptor class B type 1 (SRB1). Consistent with this, galectin-12 knockdown inhibited foam cell formation in human macrophages. In addition, the ablation of galectin-12 promoted M2 macrophage polarization in human and murine macrophages as evidenced by the upregulation of the M2 marker genes, CD206 and CD163, and downregulation of the M1 cytokines, tumor necrosis factor α (TNF- α), interleukin-6 (IL-6), and MCP-1. Moreover, the ablation of galectin-12 decreased atherosclerosis formation in DKO mice. Based on these results, we propose galectin-12 as a potential therapeutic target for atherosclerosis.
Highlights
Atherosclerosis is considered a chronic disease involving a persistent inflammatory response to injured arterial walls, which may be caused by dyslipidemia, diabetes, and/or hypertension [1,2]
We found that the ablation of galectin-12 decreased the secretion of monocyte chemoattractant protein-1 (MCP-1), TNF-α, and IL-6 in lipopolysaccharide (LPS)—and saturated fatty-acid-stimulated macrophages [7,8], suggesting that galectin-12 may potentially play a role in the pathogenesis of atherosclerosis
To determine whether galectin-12 may be involved in the pathogenesis of atherosclerosis, we measured leptin concentration in the sera of galectin-12 wild type (Gal12+/+) and knockout (Gal12−/−) mice
Summary
Atherosclerosis is considered a chronic disease involving a persistent inflammatory response to injured arterial walls, which may be caused by dyslipidemia, diabetes, and/or hypertension [1,2]. In the process of atherosclerosis, endothelial dysfunction results in the accumulation of fat in arterial walls, activating innate and adaptive immune responses that lead to inflammation [3]. The vicious cycle formed between OxLDL and the inflammatory cytokines (TNF-α and IL-6) from macrophages in the subendothelial space results in a persistent inflammatory response that promotes atherosclerosis [4]. Galectin-12 is gaining increased attention because of its involvement in the regulation of lipid metabolism, insulin sensitivity, and glucose tolerance. The negative regulation of M2 macrophage polarization by galectin-12 causes enhanced inflammation and decreases insulin sensitivity in adipocytes [8]. It remains unknown whether galectin-12 knockout could ameliorate atherosclerosis through the downregulation of chronic inflammation. We sought to clarify the mechanisms whereby galectin-12 participates in the pathogenesis of atherosclerosis
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