Abstract:
:The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosis. Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target. Regulation of CTGF expression at the promoter level has been studied extensively, but it is unknown how CTGF transcripts are regulated at the posttranscriptional level. Here we provide several lines of evidence to show that CTGF is importantly regulated by 2 major cardiac microRNAs (miRNAs), miR-133 and miR-30. First, the expression of both miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart disease and in human pathological left ventricular hypertrophy. Second, in cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, which was accompanied by decreased production of collagens. Fourth, we show that CTGF is a direct target of these miRNAs, because they directly interact with the 3' untranslated region of CTGF. Taken together, our results indicate that miR-133 and miR-30 importantly limit the production of CTGF. We also provide evidence that the decrease of these 2 miRNAs in pathological left ventricular hypertrophy allows CTGF levels to increase, which contributes to collagen synthesis. In conclusion, our results show that both miR-133 and miR-30 directly downregulate CTGF, a key profibrotic protein, and thereby establish an important role for these miRNAs in the control of structural changes in the extracellular matrix of the myocardium.
journal_name
Circ Resjournal_title
Circulation researchauthors
Duisters RF,Tijsen AJ,Schroen B,Leenders JJ,Lentink V,van der Made I,Herias V,van Leeuwen RE,Schellings MW,Barenbrug P,Maessen JG,Heymans S,Pinto YM,Creemers EEdoi
10.1161/CIRCRESAHA.108.182535subject
Has Abstractpub_date
2009-01-30 00:00:00pages
170-8, 6p following 178issue
2eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.108.182535journal_volume
104pub_type
杂志文章abstract::Smaller Ca2+ transients and systolic dysfunction in heart failure (HF) can be largely explained by reduced total sarcoplasmic reticulum (SR) Ca2+ content ([Ca]SRT). However, it is unknown whether low [Ca]SRT is manifest as reduced: (1) intra-SR free [Ca2+] ([Ca2+]SR), (2) intra-SR Ca2+ buffering, or (3) SR volume (as ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.107.152140
更新日期:2007-10-12 00:00:00
abstract::We examined whether albumin-derived advanced glycosylation end products (AGEs) downregulate the expression of endothelial nitric oxide synthase (NOS). Significant reductions in NOS activity and cGMP levels in bovine aortic endothelial cells were observed when exposed to different concentrations of albumin-derived AGEs...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.3.e50
更新日期:2000-02-18 00:00:00
abstract::It has been reported that immunization against tonin normalizes blood pressure, and that sialoadenectomy, during which the tonin-rich salivary glands are removed, decreases blood pressure in one-kidney, one-clip hypertension. To investigate the role of tonin on this form of hypertension further, we actively immunized ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.55.5.580
更新日期:1984-11-01 00:00:00
abstract::Mitochondria play a key role in determining cell fate during exposure to stress. Their role during ischemia/reperfusion is particularly critical because of the conditions that promote both apoptosis by the mitochondrial pathway and necrosis by irreversible damage to mitochondria in association with mitochondrial perme...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.RES.0000087542.26971.D4
更新日期:2003-08-22 00:00:00
abstract::On endothelial cells, thrombin binds to thrombomodulin (TM), an integral membrane-bound glycoprotein, and to protease-activated receptors (PARs). Thrombin binding to TM modulates endothelial cell and smooth muscle cell proliferation mediated through PAR1. We studied the phosphorylation and nuclear translocation of ext...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh0701.088769
更新日期:2001-04-13 00:00:00
abstract::This study examines the cellular basis and specificity of the effects of adenosine on early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and triggered activity (TA) induced by various drugs with different mechanisms of action. Membrane potential and currents were measured in isolated guinea pig ve...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.70.4.743
更新日期:1992-04-01 00:00:00
abstract::The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.119.315408
更新日期:2020-02-14 00:00:00
abstract::Nuclear factor kappa B (NF-kappaB) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-kappaB suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-kappaB super-repressor IkappaBalphaDeltaN (T...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.107.150474
更新日期:2007-08-03 00:00:00
abstract::Understanding relationships between heart failure and arrhythmias, important causes of suffering and sudden death, remains an unmet goal for biomedical researchers and physicians. Evidence assembled over the past decade supports a view that activation of the multifunctional Ca(2+) and calmodulin-dependent protein kina...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.111.243956
更新日期:2012-06-08 00:00:00
abstract::Hypertrophied cardiac myocytes exhibit prolonged action potentials and decreased transient outward potassium current (I(to)). Because Kv4.3 is a major contributor to I:(to), we studied regulation of its expression in neonatal rat cardiac myocytes in response to the known stimulators of cardiac myocyte hypertrophy, ang...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.88.5.476
更新日期:2001-03-16 00:00:00
abstract::The aim of this study is to quantify the porcine coronary arterial branching pattern and to use this quantification for the interpretation of flow heterogeneity. Two casts of the coronary arterial tree were made at diastolic arrest and maximal dilation. The relation between length and diameter of arterial segments was...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.5.1200
更新日期:1992-11-01 00:00:00
abstract::The aim of this study was to determine the mechanism of action of norepinephrine (NE) on arterial baroreceptors (BRs), with the focus on regularly discharging, presumably myelinated fibers. With the use of an in vitro aortic arch/aortic nerve preparation from rats, BR single-fiber discharge was recorded simultaneously...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.3.409
更新日期:1987-09-01 00:00:00
abstract:RATIONALE:Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyo...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.304457
更新日期:2015-01-02 00:00:00
abstract::The objectives of this study were to measure action potential parameters in enzyme-dissociated, adult rat ventricular myocytes stimulated at 1 Hz, to compare these measurements with those obtained from intact ventricular tissue, and to determine myocyte and tissue responses at stimulus frequencies between 0.1 and 5 Hz...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.52.3.280
更新日期:1983-03-01 00:00:00
abstract::Nitrite has recently emerged as an important bioactive molecule, capable of conferring cardioprotection and a variety of other benefits in the cardiovascular system and elsewhere. The mechanisms by which it accomplishes these functions remain largely unclear. To characterize the dose response and corresponding cardiac...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.187005
更新日期:2009-03-27 00:00:00
abstract::Tissue repair after injury is generally inversely related to the extent of scarring, suggesting the possibility that regeneration could be promoted by interventions that inhibit scar formation. New work by Dulauroy et al has identified a myofibroblast progenitor with pericyte characteristics as an important mediator o...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.300287
更新日期:2013-01-18 00:00:00
abstract::Cardiac alpha-adrenergic receptors mediate cellular responses to norepinephrine through an undefined series of molecular events. We examined the possibility that phosphoinositide hydrolysis was stimulated through alpha-adrenergic receptors in cardiomyocytes purified from adult rat ventricle. Phosphoinositide stores we...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.57.4.532
更新日期:1985-10-01 00:00:00
abstract::Bone morphogenetic proteins (BMPs) play important roles in cardiovascular development. However, how BMP-signaling pathways regulate cardiac gene expression is less clear. We have previously identified myocardin as a cardiac and smooth muscle-specific transcriptional cofactor for serum response factor (SRF). Myocardin ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000190670.92879.7d
更新日期:2005-11-11 00:00:00
abstract::In intact porcine aorta, endothelium-derived nitric oxide released on thrombin stimulation inhibits the concomitant production of endothelin. Experiments were designed to examine the effect of hirudin (which inactivates thrombin) and the nitrovasodilators nitroglycerin and 3-morpholinosydnonimine on the spontaneous an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.6.1768
更新日期:1991-06-01 00:00:00
abstract::To test the hypothesis that the capacity to develop left ventricular (LV) hypertrophy might diminish with advancing age, we examined the hypertrophic response to ascending aortic constriction in 3 groups of adult Fischer 344 rats (9 months, 18 months, and 22 months of age). Aortic constriction was created so that aort...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.3.337
更新日期:1987-09-01 00:00:00
abstract:RATIONALE:Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIV...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.300350
更新日期:2013-03-15 00:00:00
abstract::The sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) plays a critical role in the contractile performance of cardiac and slow-twitch skeletal muscle by restoring cytosolic calcium to low resting levels during the contractile cycle. We have previously shown that SERCA2 expression in the heart is altered by a number of pat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.4.622
更新日期:1993-10-01 00:00:00
abstract::Hypercholesterolemia induces atheroma formation, and the concentration of sphingomyelin is increased compared with that in the normal aortic intima-media. The aortic intima-media sphingomyelin concentration appears to increase exponentially with time on the cholesterol diet. Moreover, the entry rate of serum sphingomy...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.36.2.294
更新日期:1975-02-01 00:00:00
abstract::The contractile response of the aged adult heart to beta-adrenergic stimulation is known to be reduced compared with the young adult heart. Since endogenous adenosine exerts an antiadrenergic action in the heart, this study was undertaken to determine if the basal endogenous level of myocardial adenosine increases wit...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.5.1381
更新日期:1990-05-01 00:00:00
abstract::We evaluated the contribution of intramural electrical events in initiation and maintenance of ventricular tachycardia in 15 dogs 3-8 days after either permanent (n = 2) or transient (n = 13) coronary artery occlusion. Seven of the dogs (47%) demonstrated eight distinct monomorphic ventricular tachycardia patterns whi...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.56.5.736
更新日期:1985-05-01 00:00:00
abstract::We studied the individual and combined effects of extracellular acidosis and increases in extracellular potassium on action potential characteristics and conduction in order to gain a better understanding of the effects of acute ischemia. At each level of potassium between 2.7 and 17 mm, acidosis induced by increasing...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.51.5.614
更新日期:1982-11-01 00:00:00
abstract::The transcription factor nuclear factor-kappaB (NF-kappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes involved in endothelial activation. Although recent reports have documented the contribution of NF-kappaB to apoptosis, it is still controversial. Especially, the r...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.9.974
更新日期:2000-05-12 00:00:00
abstract::The average lifespan of humans is increasing, and with it the percentage of people entering the 65 and older age group is growing rapidly and will continue to do so in the next 20 years. Within this age group, cardiovascular disease will remain the leading cause of death, and the cost associated with treatment will co...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.111.246876
更新日期:2012-04-13 00:00:00
abstract::We have previously shown that a cryoactivatable inactive form of renin, which we have tentatively termed prorenin, occurs in human plasma. Plasma prorenin is measured by subtracting the endogenous plasma renin activity (PRA) from the total renin activity measured after cryoactivation. Cryoactivation is accomplished by...
journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:1977-05-01 00:00:00
abstract:RATIONALE:Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biolo...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.302476
更新日期:2014-04-25 00:00:00