MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease

Hartmann, Dorothee; Fiedler, Jan; Sonnenschein, Kristina; Just, Annette; Pfanne, Angelika; Zimmer, Karina; Remke, Janet; Foinquinos, Ariana; Butzlaff, Malte; Schimmel, Katharina; Maegdefessel, Lars; Hilfiker‐Kleiner, Denise; Lachmann, Nico; Schober, Andreas; Froese, Natali; Heineke, Joerg; Bauersachs, Johann; Bátkai, Sándor; Thum, Thomas

doi:10.1161/circulationaha.116.022478

Cited by 48 publications

(46 citation statements)

References 65 publications

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“…In our study, we demonstrate that the AKT/GSK3b signalling pathway is involved in TPPU-regulated miR-126 expression, thereby promoting EPC function. The most well-studied target genes that related to angiogenesis of miR-126 include VEGFA, PIK3R2 and SPRED1 as above mentioned [15,16]. Interestingly, previous study has also reported that miR-126 regulates AKT signalling pathway by activating its target gene PIK3R2, another important target gene of miR-126 that closely related to angiogenesis [36].…”

Section: Discussionmentioning

confidence: 97%

TPPU enhanced exercise‐induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction

Guo

Luo

Zhang

et al. 2017

J Cellular Molecular Medi

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Exercise training (ET) is a safe and efficacious therapeutic approach for myocardial infarction (MI). Given the numerous benefits of exercise, exercise‐induced mediators may be promising treatment targets for MI. C57BL/6 mice were fed 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidine‐4‐yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHI), to increase epoxyeicosatrienoic acid (EET) levels, for 1 week before undergoing MI surgery. After 1‐week recovery, the mice followed a prescribed exercise programme. Bone marrow‐derived endothelial progenitor cells (EPCs) were isolated from the mice after 4 weeks of exercise and cultured for 7 days. Angiogenesis around the ischaemic area, EPC functions, and the expression of microRNA‐126 (miR‐126) and its target gene Spred1 were measured. The results were confirmed in vitro by adding TPPU to EPC culture medium. ET significantly increased serum EET levels and promoted angiogenesis after MI. TPPU enhanced the effects of ET to reduce the infarct area and improve cardiac function after MI. ET increased EPC function and miR‐126 expression, which were further enhanced by TPPU, while Spred1 expression was significantly down‐regulated. Additionally, the protein kinase B/glycogen synthase kinase 3β (AKT/GSK3β) signalling pathway was activated after the administration of TPPU. EETs are a potential mediator of exercise‐induced cardioprotection in mice after MI. TPPU enhances exercise‐induced cardiac recovery in mice after MI by increasing EET levels and promoting angiogenesis around the ischaemic area.

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Section: Discussionmentioning

confidence: 97%

TPPU enhanced exercise‐induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction

Guo

Luo

Zhang

et al. 2017

J Cellular Molecular Medi

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“…2). GATA2 is essential for HSC emergence from hemogenic endothelium (de Pater et al, 2013;Gao et al, 2013;Johnson et al, 2012), for HSC function (Lim et al, 2012;Ling et al, 2004;Rodrigues et al, 2005) and for myelo-erythroid progenitor differentiation (Johnson et al, 2015;Rodrigues et al, 2008;Mehta et al 2017); it is also implicated in controlling endothelial cell (Dorfman et al, 1992;Hartmann et al, 2016;Johnson et al, 2012;Linnemann et al, 2011) and neuronal (Craven et al, 2004;El Wakil et al, 2006;Kala et al, 2009;Lahti et al, 2016) functions. As proerythroblasts begin to mature into erythrocytes, GATA1 replaces GATA2 at Kit chromatin sites (Fig.…”

Section: Stem Cell Factor Synthesis and Mechanisms Of Actionmentioning

confidence: 99%

Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

et al. 2018

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Hemoglobin-expressing erythrocytes (red blood cells) act as fundamental metabolic regulators by providing oxygen to cells and tissues throughout the body. Whereas the vital requirement for oxygen to support metabolically active cells and tissues is well established, almost nothing is known regarding how erythrocyte development and function impact regeneration. Furthermore, many questions remain unanswered relating to how insults to hematopoietic stem/progenitor cells and erythrocytes can trigger a massive regenerative process termed 'stress erythropoiesis' to produce billions of erythrocytes. Here, we review the cellular and molecular mechanisms governing erythrocyte development and regeneration, and discuss the potential links between these events and other regenerative processes.

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“…GATA-2 regulates multiple EC specific genes as well as miR-126 and miR-221. Systemic miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved re-endothelialization of injured carotid arteries in vivo [ 97 ].…”

Section: Anatomical Proximity Of Ec and Vsmcmentioning

confidence: 99%

RNAi therapy to the wall of arteries and veins: anatomical, physiologic, and pharmacological considerations

2017

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BackgroundCardiovascular disease remains a major health care challenge. The knowledge about the underlying mechanisms of the respective vascular disease etiologies has greatly expanded over the last decades. This includes the contribution of microRNAs, endogenous non-coding RNA molecules, known to vastly influence gene expression. In addition, short interference RNA has been established as a mechanism to temporarily affect gene expression. This review discusses challenges relating to the design of a RNA interference therapy strategy for the modulation of vascular disease. Despite advances in medical and surgical therapies, atherosclerosis (ATH), aortic aneurysms (AA) are still associated with high morbidity and mortality. In addition, intimal hyperplasia (IH) remains a leading cause of late vein and prosthetic bypass graft failure. Pathomechanisms of all three entities include activation of endothelial cells (EC) and dedifferentiation of vascular smooth muscle cells (VSMC). RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH, AA or IH. Successful RNAi delivery to the vessel wall faces multiple obstacles. These include the challenge of cell specific, targeted delivery of RNAi, anatomical barriers such as basal membrane, elastic laminae in arterial walls, multiple layers of VSMC, as well as adventitial tissues. Another major decision point is the route of delivery and potential methods of transfection. A plethora of transfection reagents and adjuncts have been described with varying efficacies and side effects. Timing and duration of RNAi therapy as well as target gene choice are further relevant aspects that need to be addressed in a temporo-spatial fashion.ConclusionsWhile multiple preclinical studies reported encouraging results of RNAi delivery to the vascular wall, it remains to be seen if a single target can be sufficient to the achieve clinically desirable changes in the injured vascular wall in humans. It might be necessary to achieve simultaneous and/or sequential silencing of multiple, synergistically acting target genes. Some advances in cell specific RNAi delivery have been made, but a reliable vascular cell specific transfection strategy is still missing. Also, off-target effects of RNAi and unwanted effects of transfection agents on gene expression are challenges to be addressed. Close collaborative efforts between clinicians, geneticists, biologists, and chemical and medical engineers will be needed to provide tailored therapeutics for the various types of vascular diseases.

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MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease

Abstract: GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Hence, modulation of GATA2 and its targets miR-126 and miR-221 is a promising therapeutic strategy for treatment of many vascular diseases.

Cited by 48 publications

References 65 publications

TPPU enhanced exercise‐induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction

TPPU enhanced exercise‐induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction

Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

RNAi therapy to the wall of arteries and veins: anatomical, physiologic, and pharmacological considerations

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