Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice

Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice.

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Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice

PLoS ONE ◽

10.1371/journal.pone.0143396 ◽

2015 ◽

Vol 10 (11) ◽

pp. e0143396 ◽

Cited By ~ 35

Author(s):

Michishige Terasaki ◽

Munenori Hiromura ◽

Yusaku Mori ◽

Kyoko Kohashi ◽

Masaharu Nagashima ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Diabetic Mice ◽

Macrophage Foam Cell ◽

Sodium Glucose Cotransporter ◽

Type 2 Diabetic

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Macrophage-foam cell formation in streptozotocin-induced diabetic mice: Stimulatory effect of glucose

Atherosclerosis ◽

10.1016/j.atherosclerosis.2005.02.018 ◽

2005 ◽

Vol 183 (1) ◽

pp. 25-33 ◽

Cited By ~ 41

Author(s):

T HAYEK ◽

K HUSSEIN ◽

M AVIRAM ◽

R COLEMAN ◽

S KEIDAR ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Diabetic Mice ◽

Macrophage Foam Cell ◽

Effect Of Glucose

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Reduction in ABCG1 in Type 2 Diabetic Mice Increases Macrophage Foam Cell Formation

Journal of Biological Chemistry ◽

10.1074/jbc.m510952200 ◽

2006 ◽

Vol 281 (30) ◽

pp. 21216-21224 ◽

Cited By ~ 66

Author(s):

Jeremy P. Mauldin ◽

Suseela Srinivasan ◽

Anny Mulya ◽

Abraham Gebre ◽

John S. Parks ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Diabetic Mice ◽

Macrophage Foam Cell ◽

Type 2 Diabetic

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Chondroitin Sulfate N -acetylgalactosaminyltransferase-2 Impacts Foam Cell Formation and Atherosclerosis by Altering Macrophage Glycosaminoglycan Chain

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315789 ◽

2021 ◽

Vol 41 (3) ◽

pp. 1076-1091

Author(s):

Imam Manggalya Adhikara ◽

Keiko Yagi ◽

Dyah Samti Mayasari ◽

Yoko Suzuki ◽

Koji Ikeda ◽

...

Keyword(s):

Chondroitin Sulfate ◽

Foam Cell ◽

Oxidized Ldl ◽

Scavenger Receptor ◽

Cell Formation ◽

Density Lipoprotein ◽

Peritoneal Macrophages ◽

Metabolic Phenotype ◽

Foam Cell Formation ◽

Macrophage Foam Cell

Objective: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N -acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2 −/− /LDLr −/− (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2 +/+ /LDLr −/− littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36—an important macrophage membrane scavenger receptor—was differentially regulated. Conclusions: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

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Abstract 126: Chlamydia Pneumoniae Induces Foam Cell Formation Of Macrophages By Activating The TLR4/TRIF/IRF3 Pathway

Circulation ◽

10.1161/circ.116.suppl_16.ii_2-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Shuang Chen ◽

Rosalinda Sorrentino ◽

Kenichi Shimada ◽

Timothy Crother ◽

Moshe Arditi

Keyword(s):

Transcriptional Control ◽

Chlamydia Pneumoniae ◽

Foam Cell ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cells ◽

Peritoneal Macrophages ◽

Foam Cell Formation ◽

Toll Like Receptors ◽

Macrophage Foam Cell

Background: Chlamydia pneumoniae (CP) induces macrophage foam cell formation (FCF), a key event in early atherosclerosis, in the presence of low-density lipoprotein (LDL). Recent studies have indicated the role of Toll-Like Receptors in atherogenesis. Liver X receptors (LXR) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism and determinants of atherosclerosis. Induction of LXR-activated genes has also been shown to influence the pathogen pattern recognition activity of the Toll-like receptors 3 and 4 (TLR3/4). The TLR and the LXR pathways converge on the transcription factor IRF3. Objective: We hypothesized that TLR and the LXR and IRF3 pathways participate in CP infection mediated FCF and acceleration of atherosclerosis, and that the MyD88- independent pathway via TLR4/TRIF and IRF3 play a role in this acceleration. Methods: Peritoneal macrophages were isolated from C57BL/6 wild type (WT) mice, IRF3 −/− mice, TLR4 −/− mice and TRIF −/− mice. Cells were treated with UV killed CP (UVCP, 5x10 5 IFU) with or without ox-LDL (100 μg/ml) in the presence or absence of LXR agonist GW3965 (2nM). LPS (10 ng/ml) and PolyI:C (1μg/ml) were used as positive controls as TLR4 and TLR3 ligands, respectively. FCF was examined by Oil Red O staining. The percentages of foam cells in total macrophages were quantified. Results : FCF was significantly reduced in IRF3−/− cells compared with WT cells stimulated with UVCP plus ox-LDL. Foam cells induced by LPS with ox-LDL were also significantly reduced in IRF3−/− cells compared to WT cells (p<0.05). Furthermore, the synthetic LXR agonist GW3965 significantly diminished CP induced FCF in WT cells. FCF was significantly reduced in TLR4−/− and TRIF−/− macrophages compared to WT cells when stimulated with UVCP with ox-LDL (p<0.05). Conclusion : Chlamydia pneumoniae infection can activate the TLR4/TRIF/IRF3 pathway and does play an important role in CP- mediated foam cell formation in macrophages. Therefore, infections such as the one caused by CP, can trigger the TLR4/TRIF/IRF3 pathway leading to the down regulation of LXRs and shifting of cholesterol transport toward pro-foam cell production and thereby accelerating atherogenesis.. Supported by NIH grants AI 067995 and HL66436 to MA.

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Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21072275 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2275 ◽

Cited By ~ 1

Author(s):

Michał Wiciński ◽

Karol Górski ◽

Eryk Wódkiewicz ◽

Maciej Walczak ◽

Magdalena Nowaczewska ◽

...

Keyword(s):

Lipid Metabolism ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Atheromatous Plaque ◽

Macrophage Foam Cell ◽

Serum Triglycerides ◽

Dipeptidyl Peptidase 4 ◽

Blood Pressure Treatment ◽

Glucagon Like Peptide 1

Vildagliptin is a representative of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, antihyperglycemic drugs, approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. By inhibiting enzymatic decomposition, DPP-4 inhibitors increase the half-life of incretins such as GLP-1 (Glucagon-like peptide-1) and GIP (Gastric inhibitors polypeptide) and prolong their action. Some studies present results suggesting the anti-sclerotic and vasculoprotective effects of vildagliptin reaching beyond glycemic control. Vildagliptin is able to limit inflammation by suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway and proinflammatory agents such as TNF-α (tumor necrosis factor α), IL-1β (Interleukin-1β), and IL-8 (Interleukin 8). Moreover, vildagliptin regulates lipid metabolism; attenuates postprandial hypertriglyceridemia; and lowers serum triglycerides, apolipoprotein B, and blood total cholesterol levels. This DPP-4 inhibitor also reduces macrophage foam cell formation, which plays a key role in atheromatous plaque formation and stability. Vildagliptin reduces vascular stiffness via elevation of nitric oxide synthesis, improves vascular relaxation, and results in reduction in both systolic and diastolic blood pressure. Treatment with vildagliptin lowers the level of PAI-1 presenting possible antithrombotic effect. By affecting the endothelium, inflammation, and lipid metabolism, vildagliptin may affect the development of atherosclerosis at its various stages. The article presents a summary of the studies assessing vasculoprotective effects of vildagliptin with special emphasis on atherogenesis.

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Faculty Opinions recommendation of A CD36-dependent signaling cascade is necessary for macrophage foam cell formation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1040613.489620 ◽

2006 ◽

Author(s):

Axel Nohturfft

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Signaling Cascade ◽

Foam Cell Formation ◽

Macrophage Foam Cell

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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 ◽

10.3390/biomedicines9070832 ◽

2021 ◽

Vol 9 (7) ◽

pp. 832

Author(s):

Michishige Terasaki ◽

Hironori Yashima ◽

Yusaku Mori ◽

Tomomi Saito ◽

Yoshie Shiraga ◽

...

Keyword(s):

Gene Expression ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

U937 Cells ◽

Cyclin Dependent Kinase ◽

Macrophage Foam Cell ◽

Cyclin Dependent Kinase 5 ◽

Gip Receptor ◽

Cd36 Gene

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr−/−) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala2]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused subcutaneously with [D-Ala2]GIP(1–42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr−/− mice infused with [D-Ala2]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 ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression 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 effects of [D-Ala2]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor.

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