Abstract
Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases. Aged garlic extract (AGE) has been reported to ameliorate atherosclerosis, although its mode of action remains unclear. We found that AGE increased the mRNA or protein levels of arginase1 (Arg1), interleukin-10 (IL-10), CD206 and hypoxia-inducible factor 2α (HIF2α) and decreased that of CD68, HIF1α and inducible nitric oxide synthase in the aorta and spleen of apolipoprotein E knockout mice. We also found that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, increased the level of IL-10-induced Arg1 mRNA and the extent of M2c-like macrophage polarization in vitro. In addition, S1PC increased the population of M2c-like macrophages, resulting in suppressed the population of M1-like macrophages and decreased lipopolysaccharide-induced production of pro-inflammatory cytokines. These effects were accompanied by prolonged phosphorylation of the IL-10 receptor α (IL-10Rα) and signal transducer and activator of transcription 3 (STAT3) that inhibited the interaction between IL-10Rα and Src homology-2-containing inositol 5’-phosphatase 1 (SHIP1). In addition, administration of S1PC elevated the M2c/M1 macrophage ratio in senescence-accelerated mice. These findings suggest that S1PC may help improve atherosclerosis due to its anti-inflammatory effect to promote IL-10-induced M2c macrophage polarization.
Highlights
Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases
Aged garlic extract (AGE) significantly suppressed the levels of Cd68 and Hif1α mRNA, out of five M1 macrophage marker genes (Cd68, Tnfα, Il-18, Hif1α, and Ccl5), in the whole aorta (Fig. 1b)
These results suggested the possibility that AGE retards the progression of atherosclerosis partly through altering the M1/M2 macrophage ratio in several tissues
Summary
Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases. S1PC increased the population of M2c-like macrophages, resulting in suppressed the population of M1-like macrophages and decreased lipopolysaccharide-induced production of pro-inflammatory cytokines These effects were accompanied by prolonged phosphorylation of the IL-10 receptor α (IL-10Rα) and signal transducer and activator of transcription 3 (STAT3) that inhibited the interaction between IL-10Rα and Src homology-2-containing inositol 5’-phosphatase 1 (SHIP1). The resulting chronic inflammation promotes the release of damage-associated molecular patterns (DAMPs), such as nucleic acids and proteins from dead cells, as well as senescence-associated secretory phenotype (SASP) factors, such as inflammatory cytokines, growth factors, and proteases from senescent cells These accelerate vascular aging by creating a positive feedback loop and eventually exacerbating plaque formation[8,9]. The dimerized STAT3 translocates to the nucleus and binds to the promoter region of IL-10-responsive genes, resulting in augmented transcription of M2c macrophage-associated g enes[31,33,34]
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