Abstract:
RATIONALE:We studied a possibility that shRNAs can lead to transcriptional gene activation at the promoter level via epigenetic mechanism. OBJECTIVE:The purpose of this study was to test the effects on vascular endothelial growth factor (VEGF-A) expression by promoter targeted small hairpin RNAs (shRNAs) in vitro and in experimental animals in vivo using stable local lentiviral gene transfer. METHODS AND RESULTS:One shRNA was identified which strongly increased VEGF-A expression in C166 endothelial cells at mRNA and protein level whereas another shRNA decreased VEGF-A expression. Quantitative chromatin immunoprecipitation analysis revealed that the repressing shRNA caused epigenetic changes, which increased nucleosome density within the promoter and transcription start site and led to repression of VEGF-A expression. Epigenetic changes caused by the activating shRNA were opposite to those caused by the repressing shRNA. These results were confirmed in vivo in an ischemic mouse hindlimb model after local gene transfer where VEGF-A upregulation achieved by promoter-targeted shRNA increased vascularity and blood flow. CONCLUSIONS:We show that lentivirus-mediated delivery of shRNA molecules targeted to specific regions in the mVEGF-A promoter either induce or repress VEGF-A expression via epigenetic modulation. Thus, we describe a new approach of gene therapy, epigenetherapy, based on an epigenetic mechanism at the promoter level. Controlling transcription through manipulation of specific epigenetic marks provides a novel approach for the treatment of several diseases.
journal_name
Circ Resjournal_title
Circulation researchauthors
Turunen MP,Lehtola T,Heinonen SE,Assefa GS,Korpisalo P,Girnary R,Glass CK,Väisänen S,Ylä-Herttuala Sdoi
10.1161/CIRCRESAHA.109.200774subject
Has Abstractpub_date
2009-09-11 00:00:00pages
604-9issue
6eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.109.200774journal_volume
105pub_type
杂志文章abstract::Previously, it was shown that the D enantiomer of isoidide dinitrate was 10-fold more potent than the L enantiomer and 10-fold less potent than glyceryl trinitrate for stimulating cyclic GMP accumulation and relaxation of isolated rat aorta. In the present study, these organic nitrates were tested for their ability to...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.63.4.693
更新日期:1988-10-01 00:00:00
abstract::We performed experiments to determine whether or not acetylcholine exerts a prejunctional inhibitory effect on adrenergic neurotransmission in the human blood vessel wall. Rings of human greater saphenous veins were prepared 2 to 15 hours after death and mounted for isometric tension recording in organ chambers filled...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.49.2.337
更新日期:1981-08-01 00:00:00
abstract::We have recently shown that adult canine ventricular myocytes express three distinct gap junction channel proteins, connexin40 (Cx40), connexin43 (Cx43), and connexin45 (Cx45). These proteins have unique cytoplasmic domains that likely confer connexin-specific physiological properties. To determine whether the three d...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.2.344
更新日期:1993-08-01 00:00:00
abstract::Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current stu...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000229267.77982.0d
更新日期:2006-06-23 00:00:00
abstract::Radiolabeled triiodothyronine (T3) binding to isolated nuclei was measured to compare the binding characteristics of the nuclear receptors in rabbit ventricular and atrial muscle cells. Scatchard analysis of the binding data yielded a maximum binding capacity of 170 +/- 20 fmol per mg DNA and apparent dissociation con...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.63.1.267
更新日期:1988-07-01 00:00:00
abstract::Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/L) in the presence of prazosin (100 nmol/L) for 24 hour...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000054624.03539.b4
更新日期:2003-02-07 00:00:00
abstract::The study was performed to determine whether there is a structural vascular abnormality in normotensive subjects with hypertensive relatives. We examined maximal vasodilator capacity of forearm resistance vessels in 23 normotensive young men (mean blood pressure 94 +/- 0.4 mm Hg, mean +/- SE) with hypertensive relativ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.50.5.671
更新日期:1982-05-01 00:00:00
abstract::Among the factors that might influence collateral arterial growth after arterial occlusion, the capacity to deliver blood flow in relation to metabolic need and work performance are obvious candidates. In this study in rats after superficial femoral artery ligation, we assessed collateral arterial growth (by arteriogr...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.70.3.546
更新日期:1992-03-01 00:00:00
abstract::A mathematical model for the regulation of mechanical activity in cardiac muscle has been developed based on a three-element rheological model of this muscle. The contractile element has been modeled taking into account the results of extensive mechanical tests that involved the recording of length-force and force-vel...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.69.5.1171
更新日期:1991-11-01 00:00:00
abstract::Smooth muscle expresses the Ialpha and the Ibeta isoforms of cGMP-dependent protein kinase I (cGKI). Inactivation of the murine cGKI gene prkg1 leads to multiple phenotypes and premature death at approximately 6 weeks. We reconstituted mice with the cGKIalpha or -Ibeta isozyme to test which isozyme was needed to suppo...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.107.154351
更新日期:2007-11-26 00:00:00
abstract::The positive inotropic effect of the beta-adrenoceptor agonist isoproterenol is accompanied by inhibition of phosphatase type 1 activity in myocardium. Indirect assays suggest that this effect is due to activation of protein phosphatase inhibitor-1, which inhibits phosphatase activity only when phosphorylated. To test...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.69.6.1450
更新日期:1991-12-01 00:00:00
abstract::The effect of sulfinpyrazone on endothelial injury induced by homocysteine has been studied both in vitro, using cultured human umbilical vein endothelial cells, and in vivo, using a primate model of homocysteine-induced arteriosclerosis. Oral sulfinpyrazone (250 mumol/kg body weight per day in three divided doses) in...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.53.6.731
更新日期:1983-12-01 00:00:00
abstract:RATIONALE:Although tyrosine kinases (TKs) are important for cardiac function, their relevant downstream targets in the adult heart are unknown. The ShcA docking protein binds specific phosphotyrosine (pTyr) sites on activated TKs through its N-terminal pTyr-binding (PTB) and C-terminal SH2 domains and stimulates downst...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.110.233924
更新日期:2011-01-21 00:00:00
abstract::Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.76.2.199
更新日期:1995-02-01 00:00:00
abstract::Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during p...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.1.224
更新日期:1989-07-01 00:00:00
abstract::Vessel stabilization and the inhibition of side effects such as tissue edema are essential in angiogenic gene therapy. Thus, combination gene transfers stimulating both endothelial cell and pericyte proliferation have become of interest. However, there is currently little data to support combination gene transfer in l...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.182287
更新日期:2008-11-07 00:00:00
abstract:RATIONALE:Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and ga...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.304382
更新日期:2014-09-26 00:00:00
abstract::Increases in free Mg2+ from 0.04 to 10.0 mM with constant pH 7.0 TO 0.10 M ionic strength, and 2 mM MgATP2- caused a rightward shift of the free Ca-relative ATPase relation for both cardiac skeletal myofibrils. The specific activity of cardiac myofibrillar ATPase over a wide range of free Ca2+ was, however, depressed ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.39.1.8
更新日期:1976-07-01 00:00:00
abstract::Cardiomyocyte hypertrophy is transcriptionally controlled and inhibited by glycogen synthase kinase 3beta (GSK3beta). Myocardin is a muscle-specific transcription factor with yet unknown relation to hypertrophy. Therefore, we investigated whether myocardin is sufficient to induce cardiomyocyte hypertrophy and whether ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000184684.88750.FE
更新日期:2005-09-30 00:00:00
abstract::We studied mitochondrial structure and intermediates of fatty acid metabolism in mitochondria isolated from ischemic hearts. By electron microscopy, no structural difference was detected between mitochondria isolated from control hearts and from ischemic hearts receiving glucose as the only substrate. However, major d...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.48.5.740
更新日期:1981-05-01 00:00:00
abstract:RATIONALE:The epicardium contributes to the majority of nonmyocardial cells in the adult heart. Recent studies have reported that the epicardium is derived from Nkx2.5-positive progenitors and can differentiate into cardiomyocytes. Not much is known about the relation between the myocardial and epicardial lineage durin...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.203083
更新日期:2009-08-28 00:00:00
abstract::Urea transporters have been cloned from kidney medulla (UT-A) and erythrocytes (UT-B). We determined whether UT-A proteins could be detected in heart and whether their abundance was altered by uremia or hypertension or in human heart failure. In normal rat heart, bands were detected at 56, 51, and 39 kDa. In uremic ra...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh1401.093293
更新日期:2001-07-20 00:00:00
abstract::Alpha1-adrenoceptor (alpha1-AR) stimulation increases sarcolemmal Na+-H+ exchanger (NHE) activity. The present study was designed to determine the role(s) of alpha1-AR subtype(s) in mediating this response. As an index of NHE activity, acid efflux rates (JHs) were determined in single rat ventricular myocytes loaded w...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.82.10.1078
更新日期:1998-06-01 00:00:00
abstract::Ryanodine receptor (RyR) phosphorylation by protein kinase A (PKA) may be important in modulating resting sarcoplasmic reticulum (SR) Ca2+ release, especially in heart failure. However, clear cellular data on PKA-dependent modulation of cardiac RyRs is limited because of difficulty in distinguishing between PKA effect...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh0302.105660
更新日期:2002-02-22 00:00:00
abstract::Recent pharmacological studies have shown that perivascular nerves can influence the development and function of vascular endothelial cells (ECs). However, morphological studies have not yet been carried out to investigate whether these functional changes are associated with changes in vasoactive substances in ECs. We...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.79.2.317
更新日期:1996-08-01 00:00:00
abstract::L-type Ca(2+) channel (LTCC) blockers, represented by amlodipine and verapamil, are widely used antihypertensive drugs that also have antiinflammatory activities. Plasminogen (Plg) is an important mediator of macrophage recruitment, and this role depends on its interaction with Plg receptors (Plg-Rs). Plg-Rs include h...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.200311
更新日期:2009-07-17 00:00:00
abstract::Inherited mutations and a polymorphism in minK-related peptide 1 (MiRP1) have been linked to congenital or acquired long-QT syndrome, pointing to the importance of MiRP1 in maintaining the cardiac electrical stability. We tested whether MiRP1 could affect the function of Kv4.x (x=2 and 3), the major pore-forming (alph...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh1001.090839
更新日期:2001-05-25 00:00:00
abstract::Whole-cell Ca2+ channel currents were recorded from isolated single canine Purkinje and ventricular cells to determine whether there were multiple types of Ca2+ channels in these two cell types, as in many other excitable tissues. The experimental conditions were such that currents other than Ca2+ channel currents wer...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.6.1735
更新日期:1989-12-01 00:00:00
abstract::We studied the specificity of uptake of infarct-imaging agents for reversibly or irreversibly injured myocardium independently of blood flow by using intact beating fetal mouse hearts in organ culture. Reversible injury resulted from deprivation of oxygen and glucose for 4 hours at 37 degrees C; irreversible injury, f...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.39.6.860
更新日期:1976-12-01 00:00:00
abstract::Complete knowledge of myocardial structure, metabolism, and function is crucial to understanding the response of the heart to injury such as ischemia. Increasingly, this type of knowledge is required at multiple levels, from that of the isolated myocyte to the functioning organism, to provide basic scientists and clin...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.RES.0000103863.40055.E8
更新日期:2003-12-12 00:00:00