Dimethylfumarate attenuates restenosis after acute vascular injury by cell-specific and Nrf2-dependent mechanisms

Abstract

Excessive proliferation of vascular smooth muscle cells (VSMCs) and incomplete re-endothelialization is a major clinical problem limiting the long-term efficacy of percutaneous coronary angioplasty. We tested if dimethylfumarate (DMF), an anti-psoriasis drug, could inhibit abnormal vascular remodeling via NF−E2-related factor 2 (Nrf2)-NAD(P)H quinone oxidoreductase 1 (NQO1) activity. DMF significantly attenuated neointimal hyperplasia induced by balloon injury in rat carotid arteries via suppression of the G1 to S phase transition resulting from induction of p21 protein in VSMCs. Initially, DMF increased p21 protein stability through an enhancement in Nrf2 activity without an increase in p21 mRNA. Later on, DMF stimulated p21 mRNA expression through a process dependent on p53 activity. However, heme oxygenase-1 (HO-1) or NQO1 activity, well-known target genes induced by Nrf2, were dispensable for the DMF induction of p21 protein and the effect on the VSMC proliferation. Likewise, DMF protected endothelial cells from TNF-α-induced apoptosis and the dysfunction characterized by decreased eNOS expression. With knock-down of Nrf2 or NQO1, DMF failed to prevent TNF-α-induced cell apoptosis and decreased eNOS expression. Also, CD31 expression, an endothelial specific marker, was restored in vivo by DMF. In conclusion, DMF prevented abnormal proliferation in VSMCs by G1 cell cycle arrest via p21 upregulation driven by Nrf2 and p53 activity, and had a beneficial effect on TNF-α-induced apoptosis and dysfunction in endothelial cells through Nrf2–NQO1 activity suggesting that DMF might be a therapeutic drug for patients with vascular disease.

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

“…248 Application of DMF can confer neuroprotection, reduce macrophage inflammation, and increase IL-10 production in mouse models of chronic experimental autoimmune encephalomyelitis. 253, 255 DMF also reduced intimal hyperplasia in a model of vascular injury, in an Nrf2-dependent mechanism involving upregulation of p21 Cip1 256 . The effects of Nrf2-inducing compounds such as DMF are not necessarily specific for HO-1, as Nrf2 regulates multiple effector enzymes.…”

Sulforaphane inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling independent of Nrf2 activation

“…Nrf2 activators have been shown to exhibit anti-proliferative effects in vitro and in vivo , in part, through Nrf2-mediated upregulation of HO-1 [50–54]. To determine whether SFN-induced Nrf2/HO-1 and/or mTOR signaling contribute to inhibition of PDGF receptor signaling, VSMCs were subjected to target-specific downregulation of Nrf2 using specific siRNA.…”

“…However, under these conditions, SFN-mediated inhibition of PDGF-induced cyclin D1 expression and key proliferative signaling remains essentially the same, suggesting that SFN-mediated Nrf2 activation does not play an intermediary role toward suppressing PDGF-induced VSMC proliferation. At this juncture, it is important to note that pharmacological agents such as curcumin, trans-resveratrol, sulfasalazine (anti-inflammatory/immune-modulatory agent), and dimethylfumarate (an anti-psoriasis drug) inhibit VSMC proliferation in vitro and in vivo presumably through Nrf2-mediated upregulation of HO-1, as reported in recent studies [50–54]. However, none of these studies has utilized Nrf2 gene-silencing strategy to support an obligatory role of Nrf2 activation toward inhibition of VSMC proliferation.…”

Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters

“…They also found that DMF protected endothelial cells from TNFα-induced apoptosis and the dysfunction characterized by decreased eNOS expression. In both cases, Nrf2 expression was dispensable since BG-12 failed to prevent both TNFα-induced cell apoptosis and decreased eNOS expression under siRNA knock-down of Nrf2 [77]. They concluded that BG-12 prevented abnormal proliferation in VSMCs and had a beneficial effect on TNFα-induced apoptosis and dysfunction in endothelial cells, both beneficial effects are Nrf2-dependent [77], as summarized in Fig.…”

“…2. Schematic summary for the DMF protects TNF-α induced cell apoptosis mediated by Nrf2-NQO1 activity in human aortic cells (HAECs), reported by Oh et al [77].…”