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Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages Through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway

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Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages Through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway biomedicines Article Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway Michishige Terasaki 1,* , Hironori Yashima 1 , Yusaku Mori 2 , Tomomi Saito 1, Yoshie Shiraga 1, Raichi Kawakami 1, Makoto Ohara 1, Tomoyasu Fukui 1, Tsutomu Hirano 3 , Yuichiro Yamada 4, Yutaka Seino 4 and Sho-ichi Yamagishi 1 1 Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, Japan; [email protected] (H.Y.); [email protected] (T.S.); [email protected] (Y.S.); [email protected] (R.K.); [email protected] (M.O.); [email protected] (T.F.); [email protected] (S.-i.Y.) 2 Anti-Glycation Research Section, Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, Japan; [email protected] 3 Diabetes Center, Ebina General Hospital, Ebina 243-0433, Japan; [email protected] 4 Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan; [email protected] (Y.Y.); [email protected] (Y.S.) * Correspondence: [email protected]; Tel.: +81-3-3784-8947 Citation: Terasaki, M.; Yashima, H.; Abstract: Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an athero- Mori, Y.; Saito, T.; Shiraga, Y.; protective property in animal models. However, the effect of GIP on macrophage foam cell formation, Kawakami, R.; Ohara, M.; Fukui, T.; a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on Hirano, T.; Yamada, Y.; et al. foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient Glucose-Dependent Insulinotropic (Gipr−/−) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP Polypeptide Suppresses Foam Cell receptor, [D-Ala2]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to Formation of Macrophages through cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused Inhibition of the Cyclin-Dependent 2 Kinase 5-CD36 Pathway. Biomedicines subcutaneously with [D-Ala ]GIP(1–42) were significantly suppressed compared with vehicle-treated −/− 2021, 9, 832. https://doi.org/ mice, while these beneficial effects were not observed in macrophages isolated from Gipr mice 2 +/+ −/− 10.3390/biomedicines9070832 infused with [D-Ala ]GIP(1–42). When macrophages were isolated from Gipr and Gipr mice, and then exposed to [D-Ala2]GIP(1–42), similar results were obtained. [D-Ala2]GIP(1–42) attenuated Academic Editors: Alexei Gratchev ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression and Matteo Di Minno level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala2]GIP(1–42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the Received: 28 May 2021 effects of [D-Ala2]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam Accepted: 12 July 2021 cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor. Published: 16 July 2021 Keywords: GIP; CD36; Cdk5; GIP receptor; macrophages Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Cardiovascular disease (CVD) is one of the devasting complications in diabetes and accounts for the increased risk of mortality in these patients all over the world [1,2]. Indeed, the Emerging Risk Factors Collaboration study revealed that after adjustment for traditional Copyright: © 2021 by the authors. coronary risk factors, the risk of death from cardiovascular causes increased by 2.3-fold in Licensee MDPI, Basel, Switzerland. This article is an open access article patients with diabetes compared with non-diabetic subjects [1]. distributed under the terms and In the subendothelial space, low-density lipoprotein (LDL) is changed to oxidized conditions of the Creative Commons LDL (ox-LDL) by oxidative modifications of apolipoprotein B100, which could stimulate Attribution (CC BY) license (https:// adhesion molecule and chemokine expression within the atherosclerotic plaques, thereby creativecommons.org/licenses/by/ promoting esterification of free cholesterol to cholesteryl ester and foam cell formation 4.0/). of macrophages, one of the initial characteristic features of atherosclerotic CVD [3–5]. Biomedicines 2021, 9, 832. https://doi.org/10.3390/biomedicines9070832 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 832 2 of 10 Scavenger receptor CD36 has been shown to contribute to ox-LDL uptake by macrophages and subsequent foam cell formation within the atherosclerotic lesions [3,5]. Glucose-dependent insulinotropic polypeptide (GIP), which is one of the incretins produced by K-cells in the small intestine in response to lipids and/or sugars, has been known to promote secretion of insulin in a glucose-dependent manner [6–9]. Besides its blood glucose-lowering action, GIP has been reported to have atheroprotective actions in animal models [10–15]. Indeed, we have previously reported that chronic infusion of active GIP(1–42) attenuates aortic plaque formation in apolipoprotein E-null (Apoe−/−) mice, whose actions were totally independent of blood pressure, body weight, food intake, and plasma lipid or glucose levels [14,15]. Furthermore, ex vivo-treatment with active GIP(1–42) has also been found to suppress the foam cell formation of, and CD36 gene expression in, macrophages isolated from Apoe−/− mice [14,15]. However, the underlying molecular mechanism for the inhibitory effects of GIP on foam cell formation of macrophages remains largely unknown. In other words, how GIP could inhibit foam cell formation of, and CD36 gene expression in, macrophages are not sufficiently understood. Cyclin-dependent kinases (Cdks) have principal roles in regulation of cell cycle, tran- scription, and differentiation [16,17]. Cyclin-dependent kinase 5 (Cdk5) is considered to be unique because in contrast to other Cdk members, Cdk5 is not a modulator of cell cycle procession [18–20], but a regulator of gene modulation and cell survive [21]. Cdk5 could phosphorylate lysine–serine–proline motif of neurofilaments, which plays a crucial role in neuronal cell development, differentiation and migration in supernumerary spinal and cranial motor neurons, while its functional disorder is involved in neurodegenerative disor- ders, such as Alzheimer’s disease [21–23]. Recently, Cdk5 has been reported to contribute to endothelial cell senescence [24], and truncated regulatory subunit of Cdk5 has been shown to be accumulated within the atherosclerotic lesions, and long-term suppression of Cdk5 attenuates the progression of atherosclerosis in Apoe−/− mice by reducing the inflam- matory reactions [18]. Moreover, Cdk5 is abundantly expressed in macrophages and could mediate the lipopolysaccharide-induced inflammatory reactions [19]. Furthermore, we have recently found that advanced glycation end products (AGEs), aging molecules formed at an accelerated rate under diabetes, stimulate macrophage foam cell formation via the activation of Cdk5-CD36 pathway [25]. Since AGEs are localized in monocyte/macrophage- derived foam cells within the atherosclerotic plaques, macrophage foam cell formation evoked by AGEs could cause the atherosclerotic plaque instability and resultantly increase the risk of CVD in diabetes [26–30]. These observations suggest that the Cdk5-CD36 pathway in macrophages could be a therapeutic target for CVD. However as far as we know, there is no paper to show the effects of GIP on foam cell formation and Cdk5-CD36 pathway in macrophages. Therefore, we investigated here whether [D-Ala2]GIP(1–42), an agonist for GIP receptor, could inhibit the macrophage foam cell formation by suppressing the Cdk5-CD36 pathway via GIP receptor interaction by using macrophages extracted from [D-Ala2]GIP(1–42)-administrated GIP receptor-deficient (Gipr−/−) and Gipr+/+ mice, [D- Ala2]GIP(1–42)-treated macrophages isolated from Gipr−/− and Gipr+/+ mice, and human U937 macrophages. 2. Materials and Methods 2.1. Materials and Reagents Materials and chemical regents were purchased as follows: [D-Ala2]GIP(1–42) from Phoenix Pharmaceuticals. Inc. (Burlingame, CA, USA), a human monocytic lymphoma line, U 937 cells from JCRB (JCRB9021; Osaka, Japan), phorbol 12-myristate 13-acetate (PMA) and Roswell Park Memorial Institute (RPMI) 1640 medium from Sigma Aldrich (St. Louis, MO, USA), 1,10-dioctadecyl-3,3,30,30-tetamethylindocarbocyanine perchlorate (Dil)-ox-LDL from Highland Technology Center (Frederick, MD, USA), and a selective Cdk5 inhibitor, (R)-DRF053 was from R&D Systems, Inc. (Minneapolis, MN, USA). Biomedicines 2021, 9, 832 3 of 10 2.2. Animal Experiments The protocol and design of this experiments were approved by the Animal Care Com- mittee of Showa University (permission number: 04141) and Akita University Graduate School of Medicine (approval number: a-1-2520). All experiments, surgeries or sacrifices, were conducted with efforts to minimize the suffering using general anesthesia of isoflurane. Gipr−/− and Gipr+/+ mice were bred (backcrossed to C57BL/6J strain for >18 generations to minimize variability of gene) as described previously [31]. A total of 10 male Gipr−/− and Gipr+/+ mice, respectively, at 7 weeks old were
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