Partial Inhibition of Glycolysis Reduces Atherogenesis Independent of Intraplaque Neovascularization in Mice

Abstract

Objective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE −/ − (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE −/− Fbn1 C1039G+/− mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)–mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE −/− Fbn1 C1039G+/− mice after 10 weeks of treatment. Conclusions: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules—an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.

Small molecule 3PO inhibits glycolysis but does not bind to 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase‐3 (PFKFB3)

“…Follow-up experiments indicate that 3PO reduces Fru-2,6-P 2 levels and glycolytic flux [6]. Since then, administration of 3PO has been considered as an attractive therapeutic strategy in cancer research, acute lung injury, lung fibrosis, and atherosclerosis [22][23][24][25]. The ability of 3PO to inhibit glycolysis was confirmed in the present study.…”

Fatty-Acid-Binding Protein 4 as a Novel Contributor to Mononuclear Cell Activation and Endothelial Cell Dysfunction in Atherosclerosis

“…On the other hand, although angiogenesis is related to the thickness and stability of the plaque, the formation of atherosclerosis may be affected independently of the angiogenesis in the plaque. Inflammation and endothelial adhesion molecules may be more important [34]. In this study, FABP4 could enhance endothelial adhesion and induce endothelial dysfunction by activating ERK/JNK/STAT-1 signaling pathways and inhibiting both eNOS and SDF-1 expression in HCAECs.…”

MiR-9 Promotes Angiogenesis via Targeting on Sphingosine-1- Phosphate Receptor 1

“…Angiogenesis is considered one of the critical pathophysiological events in multiple disorders including atherosclerotic plaque rupture (Perrotta et al, 2020), cancer, and so on (Hosein et al, 2020). MiR-9 is elevated in atherosclerosis and many cancers such as breast cancer, hepatocellular carcinoma, squamous cell carcinomas, lung and colorectal carcinoma, and ovarian cancer (Laios et al, 2008;Ma et al, 2010;Zhuang et al, 2012;White et al, 2013;Drakaki et al, 2015).…”