The treatment of coronary small vessel disease (SVD) remains an unresolved issue. Drug-eluting stents (DES) have limited efficacy due to increased rates of instent-restenosis, mainly caused by late lumen loss. Drug-coated balloons (DCB) are a promising technique because native vessels remain structurally unchanged. Basel Stent Kosten-Effektivitäts Trial: Drug-Coated Balloons vs. Drug-Eluting Stents in Small Vessel Interventions (BASKET-SMALL 2) is a multicenter, randomized, controlled, noninferiority trial of DCB vs DES in native SVD for clinical endpoints. Seven hundred fifty-eight patients with de novo lesions in vessels <3 mm in diameter and an indication for percutaneous coronary intervention such as stable angina pectoris, silent ischemia, or acute coronary syndromes are randomized 1:1 to angioplasty with DCB vs implantation of a DES after successful initial balloon angioplasty. The primary endpoint is the combination of cardiac death, nonfatal myocardial infarction, and target-vessel revascularization up to 1 year. Secondary endpoints include stent thrombosis, Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding, and long-term outcome up to 3 years. Based on clinical endpoints after 1 year, we plan to assess the noninferiority of DCB compared to DES in patients undergoing primary percutaneous coronary intervention for SVD. Results will be available in the second half of 2018. This study will compare DCB and DES regarding long-term safety and efficacy for the treatment of SVD in a large all-comer population.

Background Revascularization of saphenous vein grafts (SVGs) is challenging and debated for the last few decades. The percutaneous revascularization of SVGs was reported to have poorer long-term outcomes than native coronary artery revascularization. Purpose We aim to study the peri-procedural complications and long-term outcomes of the percutaneous revascularization of SVGs in a low-middle-income country. Methods In this retrospective study, we included 110 patients who underwent percutaneous revascularization from January 2011 to March 2020 and followed them retrospectively for long-term outcomes and major adverse cardiovascular events. Results The mean age was 71 ±9, and 81% were male. The most common reason for the presentation was non-ST segment elevation myocardial infarction (NSTEMI) (46%). The mean follow-up period of the study was 48±27 months. The most common comorbidity was hypertension (86%). A drug-eluting stent (80%) was placed in most of the patients, followed by a bare-metal stent (BMS) (14%) and percutaneous balloon angioplasty (POBA) (6%). We did not find any significant difference in major adverse cardiac events (MACE) (P=0.48), target vessel revascularization (TVR) (p=0.69), and target lesion revascularization (TLR) (p=0.54) with drug-eluting stent (DES) as compared to either BMS or POBA. The mean period from coronary artery bypass grafting (CABG) to SVG percutaneous coronary intervention (PCI) was 15± 5.5 years. Multivariate Cox regression analysis showed that an acute coronary syndrome (ACS) event, stroke, and female sex were independently associated with MACE. Conclusion The long-term outcomes of SVG PCI are not affected by the types of stents. Female gender, ACS, and stroke are the independent predictors of MACE after SVG PCI, and statin therapy has a positive impact on the long-term outcomes of SVG PCI.

To evaluate the association of successive percutaneous coronary intervention (PCI) modalities with balloon angioplasty (BA), bare-metal stent (BMS), drug-eluting stents (DES), and pharmacotherapy over the last 3 decades with outcomes among patients with diabetes in routine clinical practice.

The present study assessed the impact of early administration of abciximab in female and male patients with ST-segment elevation myocardial infarction (STEMI) transferred for primary angioplasty (PPCI). Data were gathered for 1,650 consecutive patients with STEMI transferred for PPCI from hospital networks in seven countries in Europe from November 2005 to January 2007 (the EUROTRANSFER Registry population). Among 1,086 patients who received abciximab, there were 186 women and 541 men who received abciximab early (>30 min before PPCI), and 86 women and 273 men treated with late abciximab. Female patients were high-risk individuals, with advanced age and increased rate of ischemic events. Early abciximab administration was associated with enhanced patency of the infarct-related artery before PPCI, and improved epicardial flow after PPCI in both women and men. Early abciximab in women led to the decrease in ischemic events, including 30 day (adjusted OR 0.26, 95 % CI 0.10-0.69, p = 0.007) and 1 year (adjusted OR 0.37, 95 % CI 0.16-0.84, p = 0.017) mortality reduction. In contrast, the reduction in 30 day (adjusted OR 0.69, 95 % CI 0.35-1.39, p = 0.27) and 1 year (adjusted OR 0.68, 95 % CI 0.38-1.22, p = 0.19) mortality was not significant in men. The frequency of bleeding events was similar in the early abciximab group compared to the late abciximab group in both women and men. Early administration of abciximab improved patency of the infarct-related artery before and after PPCI, and led to improved survival in female patients with STEMI.

There is no consensus as to which acute myocardial infarction subtype poses a greater risk after coronary artery bypass grafting (CABG). We compared the early and the long term results of off-pump coronary artery bypass grafting (OPCAB) between patients with STEMI (group I, n = 83), and NSTEMI (group II, n = 237). Group I had higher EuroSCORE, prevalence of emergency surgery, preoperative intra-aortic balloon pump use, preoperative emergency percutaneous transluminal coronary angioplasty, and preoperative thrombolytic use than group II. There were no significant differences in 30-day mortality and major adverse cardiac and cerebrovascular event (MACCE) between groups. Overall 8-yr survival was 93% and 87% in groups I and II, respectively. Freedom from MACCE after 8 yr was 92% and 93% in groups I and II, respectively. After propensity score matching analysis, there were no significant differences in preoperative parameters, postoperative in-hospital outcomes, and long-term clinical outcomes. Surgical results of OPCAB in patients with acute myocardial infarction show good results in terms of long-term survival and freedom from MACCE, with no significant differences in clinical outcomes between STEMI and NSTEMI groups.

Percutaneous coronary intervention (PCI) is the mainstay treatment for coronary artery disease but complications such as in-stent restenosis and thrombosis remain problematic. Radiofrequency balloon angioplasty (RBA) can improve lumen dimension, fusing intimal tears, and artery dissection but is associated with higher restenosis rate.

Objective: This study aimed to clarify the novel role of homeostatic calmodulin S100B and determined whether S100B genetic variants affected atherosclerosis progression in acute myocardial infarction (AMI) patients. Methods: Plasma levels of S100B were measured systemically in AMI patients, stable angina pectoris patients, and control subjects. S100B was obtained from the human coronary artery thrombi using a thrombectomy catheter and quantified via immunohistochemical analysis, qRT-PCR and Western blot analyse. We also screened for S100B variations (rs9722, rs9984765, rs2839356, rs1051169, and rs2186358) via direct sequencing, and investigated the relationship between these variants and AMI patients in the Chinese Han population. Results: Plasma S100B levels increased significantly in AMI patients compared to the levels in stable angina pectoris patients and control subjects (119.45 ± 62.46, 161.96 ± 73.30, and 312.91 ± 127.59 pg/ml, respectively). Immunohistochemical staining results showed that S100B expression was increased in the neutrophils of coronary artery thrombi obtained from AMI patients, as compared to that in normal blood clot, and S100B expression was significantly increased in fresh thrombi tissues, as compared to that in organized thrombi tissues. Western blot and qRT-PCR analysis showed that S100B expression increased in coronary artery thrombi, as compared to that in normal blood clots. After pre-treating the neutrophils with siRAGE, the neutrophils migration induced by S100B were abolished through the NFκB-IL1β/IL6 signaling pathway. Compared to their corresponding wild-type genotypes, the S100B rs9722 variant was associated with increased susceptibility to AMI (OR = 1.35, 95%CI: 1.12-1.65, P = 0.02). Individuals with the S100B 9722 A allele had higher plasma S100B levels than those with the G allele in control subjects and AMI patients (141.70 ± 76.69 vs. 107.31 ± 56.05 and 347.13 ± 148.94 vs. 273.05 ± 133.62, respectively). Conclusions: Levels of neutrophil-derived S100B, a novel homeostatic calmodulin, were elevated in the early stages of myocardial infarction. The S100B rs9722 allele was independently associated with AMI patients in the Han Chinese population.

Introduction: Seismocardiography (SCG) records cardiac and blood-induced motions transmitted to the chest surface as vibratory phenomena. Evidences demonstrate that acute myocardial ischemia (AMI) profoundly affects the SCG signals. Multidimensional SCG records cardiac vibrations in linear and rotational dimensions, and scalar parameters of kinetic energy can be computed. We speculate that AMI and revascularization profoundly modify cardiac kinetic energy as recorded by SCG. Methods: Under general anesthesia, 21 swine underwent 90 min of myocardial ischemia induced by percutaneous sub-occlusion of the proximal left anterior descending (LAD) coronary artery and subsequent revascularization. Invasive hemodynamic parameters were continuously recorded. SCG was recorded during baseline, immediately and 80 min after LAD sub-occlusion, and immediately and 60 min after LAD reperfusion. iK was automatically computed for each cardiac cycle (iK CC ) in linear (iK Lin ) and rotational (iK Rot ) dimensions. iK was calculated as well during systole and diastole (iK Sys and iK Dia , respectively). Echocardiography was performed at baseline and after revascularization, and the left ventricle ejection fraction (LVEF) along with regional left ventricle (LV) wall abnormalities were evaluated. Results: Upon LAD sub-occlusion, 77% of STEMI and 24% of NSTEMI were observed. Compared to baseline, troponins increased from 13.0 (6.5; 21.3) ng/dl to 170.5 (102.5; 475.0) ng/dl, and LVEF dropped from 65.0 ± 0.0 to 30.6 ± 5.7% at the end of revascularization (both p < 0.0001). Regional LV wall abnormalities were observed as follows: anterior MI, 17.6% (three out of 17); septal MI, 5.8% (one out of 17); antero-septal MI, 47.1% (eight out of 17); and infero-septal MI, 29.4% (five out of 17). In the linear dimension, i K L i n C C , i K L i n S y s , and i K L i n D i a dropped by 43, 52, and 53%, respectively (p < 0.0001, p < 0.0001, and p = 0.03, respectively) from baseline to the end of reperfusion. In the rotational dimension, i K R o t C C and i K R o t S y s dropped by 30 and 36%, respectively (p = 0.0006 and p < 0.0001, respectively), but i K R o t D i a did not change (p = 0.41). All the hemodynamic parameters, except the pulmonary artery pulse pressure, were significantly correlated with the parameters of iK, except for the diastolic component. Conclusions: In this very context of experimental AMI with acute LV regional dysfunction and no concomitant AMI-related heart valve disease, linear and rotational iK parameters, in particular, systolic ones, provide reliable information on LV contractile dysfunction and its effects on the downstream circulation. Multidimensional SCG may provide information on the cardiac contractile status expressed in terms of iK during AMI and reperfusion. This automatic system may empower health care providers and patients to remotely monitor cardiovascular status in the near future.

Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury.

Objective: To report a single-center experience using drug-eluting balloon mounted stents (DES) for endovascular treatment of atherosclerotic ostial vertebral artery stenosis (OVAS). Background: Posterior circulation is affected in up to 25% of strokes, 20% of them resulting from atherosclerotic OVAS. The optimal management of symptomatic OVAS remains controversial. DES have been introduced to improve restenosis rates. Methods: We retrospectively analyzed prospectively collected data from patients with dominant OVAS who underwent endovascular treatment with second-generation DES placement. Patient demographics, clinical presentation, comorbidities, stenosis severity, stent features, technical success, complications, and imaging follow-up were assessed. Results: Thirty patients were treated, predominantly male (86.6%). Sixteen patients presented with an acute stroke or TIA and fourteen were treated on an elective basis due to symptomatic chronic stenosis and contralateral occlusion. Comorbidities included hyperlipidemia (83%), hypertension (70%) and prior stroke (63.3%). Mean ostial stenosis at presentation was 80 ± 14.8%. Twenty-one patients had contralateral VA involvement. DES deployment was technically successful in all patients using everolimus eluting stents in 30 lesions and zotarolimus eluting stents in two. One technical complication (stent migration) and three (10%) minor peri-procedural complications occurred. Complications included one asymptomatic ischemic infarct in the posterior circulation, one femoral artery thrombosis and one post-procedure altered mental status secondary to contrast induced neurotoxicity. Mean imaging follow-up was 8.8 months. Two (7.6%) patients had in-stent restenosis and underwent retreatment with angioplasty. There were no procedure-related mortalities. Conclusion: Our study confirms the feasibility of deploying DES for the treatment of ostial vertebral artery stenosis with low peri-procedural risk and low medium-term rates of re-stenosis.

Restenosis after angioplasty is a major challenge for the treatment of coronary artery diseases. Facilitation of vascular smooth muscle cell (VSMC) apoptosis may be an attractive approach to decrease the incidence of restenosis. We synthesized a 16-amino acid mitofusin-2 (Mfn-2) gene related peptide (MRSP) based on the sequence of the p21ras signature motif, the smallest functional sequence of the Mfn-2 gene with proapoptotic properties in VSMC. We investigated whether MRSP enhanced apoptotic activities to inhibit VSMC accumulation and neointimal hyperplasia in rats with carotid balloon injury.

Coronary restenosis, a major complication of percutaneous balloon angioplasty, results from neointimal proliferation of vascular smooth muscle cells (VSMCs). The sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a), specific to contractile VSMCs, has been reported previously to be involved in the control of the Ca(2+)-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal thickening in a rat carotid injury model. The aim of this study was to evaluate the potential therapeutic interest of SERCA2a gene transfer for prevention of in-stent restenosis using a ex vivo model of human left internal mammary artery (hIMA) intimal thickening. Left hIMAs, obtained at the time of aorto-coronary bypass surgeries, were subjected to balloon dilatation followed by infection for 30 min with adenoviruses encoding either human SERCA2 and green fluorescence protein (GFP) or control gene (β-galactosidase, β-gal) and GFP. Proliferation of subendothelial VSMCs and neointimal thickening were observed in balloon-injured hIMA maintained 14 days in organ culture under constant pressure and perfusion. SERCA2a gene transfer prevented vascular remodeling and significantly (P<0.01, n=5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07±0.01 vs 0.40±0.03 in β-gal-infected arteries). These findings could have potential implications for treatment of pathological in-stent restenosis.

Standard extracellular cardiovascular magnetic resonance (CMR) contrast agents (CA) do not provide differentiation between acute and older myocardial infarcts (MI). The purpose of this study was to develop a method for differentiation between acute and older myocardial infarct using myocardial late-enhancement (LE) CMR by a new, low molecular weight contrast agent.Dogs (n = 6) were studied in a closed-chest, reperfused, double myocardial infarct model. Myocardial infarcts were generated by occluding the Left Anterior Descending (LAD) coronary artery with an angioplasty balloon for 180 min, and four weeks later occluding the Left Circumflex (LCx) coronary artery for 180 min. LE images were obtained on day 3 and day 4 after second myocardial infarct, using Gd(DTPA) (standard extracellular contrast agent) and Gd(ABE-DTTA) (new, low molecular weight contrast agent), respectively. Triphenyltetrazolium chloride (TTC) histomorphometry validated existence and location of infarcts. Hematoxylin-eosin and Masson's trichrome staining provided histologic evaluation of infarcts.

Accelerated atherosclerosis diminishes the long term patency of vascular interventions, such as percutaneous coronary intervention and implantation of saphenous vein grafts. However, the cause of this accelerated atherosclerosis is unclear. In this study, we tested the hypothesis that intimal hyperplasia formed following vascular intervention promotes retention of atherogenic lipoproteins. Intimal hyperplasia was surgically induced in the mouse common carotid artery. The surgery was combined with different mouse models of hypercholesterolemia to obtain different cholesterol levels and to control the onsets of hypercholesterolemia. Three weeks after surgery, samples were immunostained for apoB lipoproteins, smooth muscle cells and leukocytes. Already at mild hypercholesterolemia (193 mg/dL), pronounced apoB lipoprotein retention was found in the extracellular matrix in both intimal hyperplasia and the injured underlying media. In contrast, minimal retention was detected in the uninjured proximal region of the same vessel, or in vessels from mice with normal cholesterol levels (81 mg/dL). Induction of aggravated hypercholesterolemia 3 weeks after surgery, when a mature intimal hyperplasia had been formed, caused a very rapid development of atherosclerotic lesions. Mechanistically, we show that lipoprotein retention was almost exclusively dependent on electrostatic interactions to proteoglycan glycosaminoglycans, and the lipoprotein retention to intimal hyperplasia could be inhibited in vivo using glycosaminoglycan-binding antibodies. Thus, formation of intimal hyperplasia following vascular intervention makes the vessel wall highly susceptible for lipoprotein retention and accelerated atherosclerosis. The increased lipoprotein retention in intimal hyperplasia can be targeted by blocking the interaction between apoB lipoproteins and glycosaminoglycans in the extracellular matrix.

Granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling after myocardial infarction, but its effect on atherosclerosis is unknown. We examined two kinds of rabbit atherosclerosis models. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were treated with G-CSF or saline for 7 days from 14 months old. The vascular injury models were created by inflating angioplasty balloon in the iliac artery of rabbits and were divided into G-CSF and saline group. G-CSF significantly reduced the stenosis score of coronary artery and lipid plaque area of thoracic aorta in WHHL-MI rabbits at 4 weeks after the treatment. In the vascular injury model, G-CSF significantly prevented an increase in neointima/media ratio at 4 weeks after the treatment. G-CSF accelerated the reendothelialization of denuded arteries, and the pretreatment with nitric oxide synthase inhibitor significantly inhibited it. These results suggest that G-CSF has a therapeutic potential for the progression of atherosclerosis.

The abnormal proliferation and migration of Vascular smooth muscle cells (VSMCs) are related to many cardiovascular diseases, including atherosclerosis, restenosis after balloon angioplasty, hypertension, etc. Myricanol is a diarylheptanoid that can be separated from the bark of Myrica rubra. It has been reported that myricanol can anti-inflammatory, anti-cancer, anti-neurodegenerative, promote autophagic clearance of tau and prevent muscle atrophy. But its potential role in the cardiovascular field remains unknown. In this study, we investigated the effect of myricanol on the proliferation and migration of VSMCs in vitro and on the intimal hyperplasia in vivo. In vitro experiments, we found myricanol can inhibit the proliferation and migration of VSMCs induced by PDGF-BB. In terms of mechanism, the preincubation of myricanol can suppress the PDGF-BB induced phosphorylation of PDGFRβ and its downstream such as PLCγ1, Src, and MAPKs. In addition, NF-kB p65 translocation was also suppressed by myricanol. In vivo experiments, we found myricanol can suppress the intimal hyperplasia after wire ligation of the carotid artery in mice. These results may provide a new strategy for the prevention and treatment of coronary atherosclerosis and post-stent stenosis in the future.

Contrast angiography is presently the standard for in vivo quantitation and morphologic evaluation of coronary atherosclerosis. Pathologic-angiographic correlation studies have shown marked angiographic underestimation of atheromatous plaques. This is particularly true in the early stages of intimal thickening and atheroma growth where media initially enlarges to accommodate the proliferative process without a chance in lumen size. The miniaturization of transducers allowed to mount them on the tip of a catheter and made it possible to position these catheters inside the arterial lumen and, for the first time, to see in vivo the vessel wall. Intravascular ultrasound is a new imaging technique with the ability to define and measure luminal areas and arterial wall components; therefore it serves as a potential tool to assess vascular wall morphology and dynamic vasomotor responses in epicardial coronary arteries. Its ability to measure luminal areas and diameters and the different components of the arterial wall has been validated by several in vitro, animal and in vivo studies. The definition of normal arterial wall by ultrasound has been defined looking at coronary arteries of young adults. It also showed that young subjects with angiographically normal vessels have a wide range of coronary intimal thickening, including occasional evidence of focal, early atheromatous lesions. Safety studies have shown it does not accelerate progression of angiographically quantifiable coronary artery disease suggesting that it can be safely utilized even in coronary arteries not undergoing interventions. The large potential of intracoronary imaging in the setting of interventional cardiology and future developments are also discussed, including the use of combined devices (ultrasound catheter-balloon angioplasty, ultrasound-atherectomy, ultrasound-laser); three dimensional reconstruction; new devices design, such as looking forward catheters; tissue characterization with the goal of differentiating between different types of plaque, and between soft plaque and thrombus; study of biomechanical properties of the atherosclerotic plaque, trying to distinguish between "good" and "bad" plaques. In conclusion, intravascular ultrasound is a powerful in vivo coronary imaging technique which may serve as a new standard for quantifying coronary atherosclerosis and offers significant potential for enhancing our understanding of the pathophysiology of coronary artery disease.

In-stent restenosis is a serious concern for patients treated through the stenting procedure, although this can be solved using drug-eluting stents and/or drug-eluting balloon catheters. However, the chemical agents released from the drug-eluting layer for inhibiting smooth muscle cell (SMC) migration are inevitably associated with damage to vascular endothelial cell (ECs). The present in vitro study used a distinct strategy, in which a smart gene (phEGR1-PKCδ, an engineered plasmid consists of an SMC-specific promoter (human early growth response 1, hEGR1 promoter) ligated with a gene encoding apoptosis-inducing protein (protein kinase C-delta, PKCδ) was incorporated into a novel gene vehicle (Au cluster-incorporated polyethylenimine/carboxymethyl hexanoyl chitosan, PEI-Au/CHC) to form the PEI-Au/CHC/phEGR1-PKCδ complex, which was proposed for the selective inhibition of SMC proliferation. It was found that the cell viability of SMCs receiving the PEI-Au/CHC/phEGR1-PKCδ complex under simulated inflammation conditions was significantly lower than that of the ECs receiving the same treatment. In addition, the PEI-Au/CHC/phEGR1-PKCδ complex did not demonstrate an inhibitory effect on EC proliferation and migration under simulated inflammation conditions. Finally, the PEI-Au/CHC/phEGR1-PKCδ complexes coated onto a balloon catheter used in percutaneous transluminal coronary angioplasty (PTCA) could be transferred to both the ECs and the SMC layer of Sprague Dawley (SD) rat aortas ex vivo. These preliminary in vitro results suggest that the newly developed approach proposed in the present study might be a potential treatment for reducing the incidence rate of in-stent restenosis and late thrombosis in the future.

Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E-deficient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insufficient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specific effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our findings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.

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.