Masashi Tanaka1, Yoshiyuki Matsuo1, Hajime Yamakage1, Shinya Masuda1, Yuko Terada1, Kazuya Muranaka1, Hiromichi Wada2, Koji Hasegawa2, Akira Shimatsu1, Noriko Satoh-Asahara3. 1. Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. 2. Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. 3. Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. Electronic address: nsatoh@kuhp.kyoto-u.ac.jp.
Abstract
OBJECTIVE: Monocytes/macrophages (Mϕ) transform into foam cells in the presence of oxidized-LDL (ox-LDL), releasing inflammatory mediators. The antiatherogenic role of a dipeptidyl peptidase-4 inhibitor is mediated, in part, through improving the unbalance of inflammatory (M1)/anti-inflammatory (M2) phenotypes in monocytes. In this study, we examined differential regulation of glucagon-like peptide-1 receptor (GLP-1R) signaling for antiatherogenesis in monocytes/Mϕ from normal-weight control subjects and obese patients. METHODS: We evaluated the effects of exendin-4 (Ex-4), a GLP-1R agonist, on ox-LDL-stimulated foam cell formation, M1/M2 cytokine production, and organelle change in primary monocytes from control subjects and obese patients and human monocytic THP-1-derived Mϕ as well. RESULTS: Here we report that Ex-4 suppressed foam cell formation and M1 cytokine expression and, interestingly, induced indicators of autophagy in ox-LDL-stimulated monocytes from control subjects. The suppressing effects on foam cell formation by Ex-4 were reversed by a cAMP inhibitor. In contrast to control subjects, Ex-4 did not induce indicators of autophagy, but did induce foam cell formation and M1 cytokine expression in monocytes from obese patients. GLP-1R expression level was comparable between control subjects and obese patients. The effects of Ex-4 on inducing indicators of autophagy and suppressing foam cell formation were observed in THP-1 Mϕ. CONCLUSIONS: These data suggest that GLP-1R signaling induces autophagy, thereby suppressing foam cell formation in non-obese subjects. In obese patients, GLP-1R stimulation increased foam cell formation and IL-6, TNF-α, and IL-1β production. Such altered signaling in monocytes of obese patients may be involved in the development of atherosclerosis.
OBJECTIVE: Monocytes/macrophages (Mϕ) transform into foam cells in the presence of oxidized-LDL (ox-LDL), releasing inflammatory mediators. The antiatherogenic role of a dipeptidyl peptidase-4 inhibitor is mediated, in part, through improving the unbalance of inflammatory (M1)/anti-inflammatory (M2) phenotypes in monocytes. In this study, we examined differential regulation of glucagon-like peptide-1 receptor (GLP-1R) signaling for antiatherogenesis in monocytes/Mϕ from normal-weight control subjects and obesepatients. METHODS: We evaluated the effects of exendin-4 (Ex-4), a GLP-1R agonist, on ox-LDL-stimulated foam cell formation, M1/M2 cytokine production, and organelle change in primary monocytes from control subjects and obesepatients and human monocytic THP-1-derived Mϕ as well. RESULTS: Here we report that Ex-4 suppressed foam cell formation and M1 cytokine expression and, interestingly, induced indicators of autophagy in ox-LDL-stimulated monocytes from control subjects. The suppressing effects on foam cell formation by Ex-4 were reversed by a cAMP inhibitor. In contrast to control subjects, Ex-4 did not induce indicators of autophagy, but did induce foam cell formation and M1 cytokine expression in monocytes from obesepatients. GLP-1R expression level was comparable between control subjects and obesepatients. The effects of Ex-4 on inducing indicators of autophagy and suppressing foam cell formation were observed in THP-1 Mϕ. CONCLUSIONS: These data suggest that GLP-1R signaling induces autophagy, thereby suppressing foam cell formation in non-obese subjects. In obesepatients, GLP-1R stimulation increased foam cell formation and IL-6, TNF-α, and IL-1β production. Such altered signaling in monocytes of obesepatients may be involved in the development of atherosclerosis.