Janus Phenomenon

Epstein, Stephen E.; Stabile, Eugenio; Kinnaird, Timothy; Lee, Cheol Whan; Clavijo, Leonardo; Burnett, Mary Susan

doi:10.1161/01.cir.0000132468.82942.f5

Cited by 108 publications

(46 citation statements)

References 99 publications

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“…Although a few previous studies have demonstrated increased arteriogenic capacity after such a delayed treatment,46, 78, 79 ours is the first to demonstrate an epigenetic mechanism. DNMT1 inhibition may also be clinically advantageous because it appears to avoid the so‐called Janus phenomenon, which refers to the conundrum created by the fact that proarteriogenic therapies also tend to promote atherosclerosis 80. To this point, DNMT1 inhibition with 5AZA reverses DNA hypermethylation induced by atheroprone shear stress17, 18 and reduces atherosclerotic plaque size 17…”

Section: Discussionmentioning

confidence: 99%

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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BackgroundArteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original “set point.” However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)–dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.Methods and ResultsIn femoral artery ligation–operated C57BL/6 mice, collateral artery segments exposed to increased shear stress without a change in flow direction (ie, nonreversed flow) exhibited global DNA hypermethylation (increased 5‐methylcytosine staining intensity) and constrained arteriogenesis (30% less diameter growth) when compared with segments exposed to both an increase in shear stress and reversed‐flow direction. In vitro, ECs exposed to a flow waveform biomimetic of nonreversed collateral segments in vivo exhibited a 40% increase in DNMT1 expression, genome‐wide hypermethylation of gene promoters, and a DNMT1‐dependent 60% reduction in proarteriogenic monocyte adhesion compared with ECs exposed to a biomimetic reversed‐flow waveform. These results led us to test whether DNMT1 regulates arteriogenic capacity in vivo. In femoral artery ligation–operated mice, DNMT1 inhibition rescued arteriogenic capacity and returned shear stress back to its original set point in nonreversed collateral segments.ConclusionsIncreased shear stress without a change in flow direction initiates arteriogenic growth; however, it also elicits DNMT1‐dependent EC DNA hypermethylation. In turn, this diminishes mechanosensing, augments shear stress set point, and constrains the ultimate arteriogenic capacity of the vessel. This epigenetic effect could impact both endogenous collateralization and treatment of arterial occlusive diseases.

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Section: Discussionmentioning

confidence: 99%

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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“…17,18 The term Janus phenomenon has been invented for the dual effect of protein (FGF, MCP-1)-, gene (VEGF, TNF)-, or cell (BMMNCs, EPC)-based therapeutic angiogenesis on progression and destabilization of atherogenesis. 4 NO appears to be a possible exception to the Janus phenomenon because it has established proneovascularization and antiatherogenic effects. However, these effects have never been investigated at the same time in the same model.…”

Section: Discussionmentioning

confidence: 99%

“…3 This potentially hazardous dual effect of therapeutic neovascularization on atherogenesis is explained by the many common pathways of both mechanisms and has been named the Janus phenomenon. 4 Impaired bioavailability of NO is a hallmark in patients with cardiovascular disease. Moreover, the enzyme endo-thelial NO synthase (eNOS) has also been shown to be essential for neovascularization.…”

mentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Overexpression Restores the Efficiency of Bone Marrow Mononuclear Cell-Based Therapy

Mees

Récalde

Loinard

et al. 2011

The American Journal of Pathology

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Bone marrow-derived mononuclear cells (BMMNCs) enhance postischemic neovascularization, and their therapeutic use is currently under clinical investigation. However, cardiovascular risk factors, including diabetes mellitus and hypercholesterolemia, lead to the abrogation of BMMNCs proangiogenic potential. NO has been shown to be critical for the proangiogenic function of BMMNCs, and increased endothelial NO synthase (eNOS) activity promotes vessel growth in ischemic conditions. We therefore hypothesized that eNOS overexpression could restore both the impaired neovascularization response and decreased proangiogenic function of BMMNCs in clinically relevant models of diabetes and hypercholesterolemia. To prevent or treat ischemic diseases, therapeutic neovascularization, the stimulation of tissue vascularization after ischemia, has recently progressed from the bench to the bedside. Strategies include transplantation of angiogenic bone marrow-derived mononuclear cells (BMMNCs) or gene transfer for systemic or local up-regulation of proangiogenic proteins. Clinical studies have demonstrated the safety, feasibility, and efficacy of intracoronary and intramuscular infusion of adult BMMNCs in patients with peripheral arterial disease, acute myocardial infarction, and ischemic cardiomyopathy. 1,2However, despite the excitement surrounding the possible clinical use of BMMNCs, in atherosclerosis, diabetes mellitus, and other risk factors for cardiovascular diseases the availability of bone marrow and progenitor cells is reduced and their function impaired to varying degrees.1,2 Moreover, the safety of BMMNCs treatment has been questioned by studies that found an increase in atherosclerotic plaque size after BMMNCs treatment. 3This potentially hazardous dual effect of therapeutic neovascularization on atherogenesis is explained by the many common pathways of both mechanisms and has been named the Janus phenomenon.

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“…Atherosclerosis is triggered and sustained by inflammation related cytokines, chemokines, adhesion molecules and by the cellular components of the immune system (Ross, 1999;Epstein et al, 2004). Cholesterol, most of it transported as a low density lipoprotein (LDL) particle in the bloodstream, supports foam cell formation in atherosclerotic plaques.…”

Section: Apolipoprotein E Inflammation and Atherosclerosismentioning

confidence: 99%

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E

Dimitrova-Shumkovska¹,

Veenman²,

Roim³

et al. 2013

Lipid Metabolism

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Janus Phenomenon

Cited by 108 publications

References 99 publications

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Endothelial Nitric Oxide Synthase Overexpression Restores the Efficiency of Bone Marrow Mononuclear Cell-Based Therapy

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E

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