Smooth muscle glucose metabolism promotes monocyte recruitment and atherosclerosis in a mouse model of metabolic syndrome
Valerie Z. Wall, … , Jennifer L. Hall, Karin E. Bornfeldt
Valerie Z. Wall, … , Jennifer L. Hall, Karin E. Bornfeldt
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e96544. https://doi.org/10.1172/jci.insight.96544.
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Research Article Vascular biology

Smooth muscle glucose metabolism promotes monocyte recruitment and atherosclerosis in a mouse model of metabolic syndrome

Abstract

Metabolic syndrome contributes to cardiovascular disease partly through systemic risk factors. However, local processes in the artery wall are becoming increasingly recognized to exacerbate atherosclerosis both in mice and humans. We show that arterial smooth muscle cell (SMC) glucose metabolism markedly synergizes with metabolic syndrome in accelerating atherosclerosis progression, using a low-density lipoprotein receptor–deficient mouse model. SMCs in proximity to atherosclerotic lesions express increased levels of the glucose transporter GLUT1. Cytokines, such as TNF-α produced by lesioned arteries, promote GLUT1 expression in SMCs, which in turn increases expression of the chemokine CCL2 through increased glycolysis and the polyol pathway. Furthermore, overexpression of GLUT1 in SMCs, but not in myeloid cells, accelerates development of larger, more advanced lesions in a mouse model of metabolic syndrome, which also exhibits elevated levels of circulating Ly6Chi monocytes expressing the CCL2 receptor CCR2. Accordingly, monocyte tracing experiments demonstrate that targeted SMC GLUT1 overexpression promotes Ly6Chi monocyte recruitment to lesions. Strikingly, SMC-targeted GLUT1 overexpression fails to accelerate atherosclerosis in mice that do not exhibit the metabolic syndrome phenotype or monocytosis. These results reveal a potentially novel mechanism whereby arterial smooth muscle glucose metabolism synergizes with metabolic syndrome to accelerate monocyte recruitment and atherosclerosis progression.

Authors

Valerie Z. Wall, Shelley Barnhart, Jenny E. Kanter, Farah Kramer, Masami Shimizu-Albergine, Neeta Adhikari, Thomas N. Wight, Jennifer L. Hall, Karin E. Bornfeldt

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Figure 3

DDC feeding in male and female Ldlr–/– mice results in dyslipidemia and features of metabolic syndrome, which are not affected by SMC GLUT1 overexpression.

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DDC feeding in male and female Ldlr–/– mice results in dyslipidemia and ...
(A) Male and female WT and SM-GLUT1 Ldlr–/– mice, 8–10 weeks of age, were fed DDC or chow for 16 weeks. DDC-fed male mice exhibited elevated plasma cholesterol (B), elevated plasma triglycerides (C), increased body weight (D), and elevated nonfasting blood glucose levels (E). (F) Glucose tolerance tests revealed impaired glucose tolerance. SM-GLUT1 overexpression did not affect any of these parameters. Results are expressed as mean ± SEM (n = 16–25 for groups in D and E, as shown in B and C; n = 10–16 in F). Female Ldlr–/– mice fed DDC develop similarly elevated plasma cholesterol (G) but exhibit a lesser degree of increased triglycerides (H), body weight gain (I), nonfasting blood glucose (J), and glucose intolerance (K), as compared with male mice. (L) HbA1c levels in male and female mice fed DDC. Results are expressed as mean ± SEM (n = 5–15 in G–K, as shown in G). Statistical analysis was performed by 1-way ANOVA (B, C, G, H) or 2-way ANOVA (D–F, I–K) with Tukey’s post hoc test; *,#P < 0.05; **,##P < 0.01; ***,###P < 0.001; ****,####P < 0.0001, where * indicates WT and # indicates SM-GLUT1 chow vs. DDC in D–F and I–K.