8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

Abstract

8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis.

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

“…Here we presented evidence about the critical role and molecular mechanism of MFN2 in regulating VSMCs proliferation during the Atherosclerosis is a complex disease which begins with eccentric thickening of the intima, which is predominantly composed of VSMCs, mesenchymal intimal cells and inflammatory cells. 2 In recent years, VSMCs proliferation has been considered as an important pathological factor in atherosclerosis. 2 Hcy is an independent risk factor of atherosclerosis.…”

Postprandial triglyceride-rich lipoproteins promote invasion of human coronary artery smooth muscle cells in a fatty-acid manner through PI3k-Rac1-JNK signaling

“…hCASMCs grown to subconfluence were stimulated with TRLs-SFA (100 g TG/mL) for various times (5,10,15,30, and 60 min). The immunoblotting method has been described previously [16].…”

Markers of Oxidative Stress in Human Milk do not Differ by Maternal BMI But are Related to Infant Growth Trajectories

“…8OHdG has been shown to affect murine macrophage signaling and function both in-vitro and in-vivo (Huh et al, 2012; Lee et al, 2009), giving credence to the hypothesis that this molecule could also affect the local environment of the infant intestine, theoretically impacting WLZ downstream.…”

“…Oral administration of 8OHdG, in a murine model of atherosclerosis, exerted powerful antiinflammatory effects which reduced plaque formation via these mechanisms in neutrophils, macrophages, and vascular smooth muscle cells (the only cell types studied) (Huh et al, 2012). Interestingly, the oral dose of 8OHdG administered to rats in that study was only 12 times greater than the estimated average dose received by an exclusively breastfed infant at 4 months of age (based on average concentration of 8OHdG detected in this study, and average milk consumption of infants at this age (Huh et al, 2012)). These studies suggest that oral 8OHdG consumed by the infant via HM may indeed alter signaling pathways in various cell types in the infant.…”