Critical role of cyclin D1 nuclear import in cardiomyocyte proliferation.

Abstract:

:Mammalian cardiomyocytes irreversibly lose their capacity to proliferate soon after birth, yet the underlying mechanisms have been unclear. Cyclin D1 and its partner, cyclin-dependent kinase 4 (CDK4), are important for promoting the G1-to-S phase progression via phosphorylation of the retinoblastoma (Rb) protein. Mitogenic stimulation induces hypertrophic cell growth and upregulates expression of cyclin D1 in postmitotic cardiomyocytes. In the present study, we show that, in neonatal rat cardiomyocytes, D-type cyclins and CDK4 were predominantly cytoplasmic, whereas Rb remained in an underphosphorylated state. Ectopically expressed cyclin D1 localized in the nucleus of fetal but not neonatal cardiomyocytes. To target cyclin D1 to the nucleus efficiently, we constructed a variant of cyclin D1 (D1NLS), which directly linked to nuclear localization signals (NLSs). Coinfection of recombinant adenoviruses expressing D1NLS and CDK4 induced Rb phosphorylation and CDK2 kinase activity. Furthermore, D1NLS/CDK4 was sufficient to promote the reentry into the cell cycle, leading to cell division. The number of cardiomyocytes coinfected with these viruses increased 3-fold 5 days after infection. Finally, D1NLS/CDK4 promoted cell cycle reentry of cardiomyocytes in adult hearts injected with these viruses, evaluated by the expression of Ki-67, which is expressed in proliferating cells in all phases of the cell cycle, and BrdU incorporation. Thus, postmitotic cardiomyocytes have the potential to proliferate provided that cyclin D1/CDK4 accumulate in the nucleus, and the prevention of their nuclear import plays a critical role as a physical barrier to prevent cardiomyocyte proliferation. Our results provide new insights into the development of therapeutics strategies to induce regeneration of cardiomyocytes. The full text of this article is available at http://www.circresaha.org.

journal_name

Circ Res

journal_title

Circulation research

authors

Tamamori-Adachi M,Ito H,Sumrejkanchanakij P,Adachi S,Hiroe M,Shimizu M,Kawauchi J,Sunamori M,Marumo F,Kitajima S,Ikeda MA

doi

10.1161/01.res.0000049105.15329.1c

subject

Has Abstract

pub_date

2003-01-10 00:00:00

pages

e12-9

issue

1

eissn

0009-7330

issn

1524-4571

journal_volume

92

pub_type

杂志文章
  • Long noncoding RNAs in patients with acute myocardial infarction.

    abstract:RATIONALE:Long noncoding RNAs (lncRNAs) constitute a novel class of noncoding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia. OBJECTIVE:To measure lncRNAs in patients with myocardi...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.115.303836

    authors: Vausort M,Wagner DR,Devaux Y

    更新日期:2014-09-12 00:00:00

  • An osteopontin-NADPH oxidase signaling cascade promotes pro-matrix metalloproteinase 9 activation in aortic mesenchymal cells.

    abstract::Osteopontin (OPN) is a cytokine upregulated in diabetic vascular disease. To better understand its role in vascular remodeling, we assessed how OPN controls metalloproteinase (MMP) activation in aortic adventitial myofibroblasts (AMFs) and A7r5 vascular smooth muscle cells (VSMCs). By zymography, OPN and tumor necrosi...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000227550.00426.60

    authors: Lai CF,Seshadri V,Huang K,Shao JS,Cai J,Vattikuti R,Schumacher A,Loewy AP,Denhardt DT,Rittling SR,Towler DA

    更新日期:2006-06-23 00:00:00

  • minK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as beta subunit of cardiac transient outward channel?

    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

    authors: Zhang M,Jiang M,Tseng GN

    更新日期:2001-05-25 00:00:00

  • Sensitization of dog and guinea pig heart myofilaments to Ca2+ activation and the inotropic effect of pimobendan: comparison with milrinone.

    abstract::We compared the effects of the newer inotropic drugs, pimobendan (UD-CG 115 BS) and milrinone (Win 47203), on the electrical, mechanical and biochemical activity of intact and detergent-skinned preparations of cardiac muscle. Both of these agents increased contractile force of guinea pig papillary muscle preparations ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.63.5.911

    authors: Fujino K,Sperelakis N,Solaro RJ

    更新日期:1988-11-01 00:00:00

  • The mechanism of coronary collateral vasoconstriction in response to cyclooxygenase blockade.

    abstract::The present study was performed to examine the mechanism by which cyclooxygenase blockade produces vasoconstriction in well-developed coronary collateral vessels. Eight dogs were studied 4 to 6 months after occlusion of the left anterior descending coronary artery (LAD) had been performed to stimulate collateral vesse...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.74.2.310

    authors: Altman JD,Bache RJ

    更新日期:1994-02-01 00:00:00

  • Smooth muscle-specific expression of the smooth muscle myosin heavy chain gene in transgenic mice requires 5'-flanking and first intronic DNA sequence.

    abstract::The smooth muscle myosin heavy chain (SM-MHC) gene encodes a major contractile protein whose expression exclusively marks the smooth muscle cell (SMC) lineage. To better understand smooth muscle differentiation at the transcriptional level, we have initiated studies to identify those DNA sequences critical for express...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.82.8.908

    authors: Madsen CS,Regan CP,Hungerford JE,White SL,Manabe I,Owens GK

    更新日期:1998-05-04 00:00:00

  • Astrocyte-derived CO is a diffusible messenger that mediates glutamate-induced cerebral arteriolar dilation by activating smooth muscle Cell KCa channels.

    abstract::Astrocyte signals can modulate arteriolar tone, contributing to regulation of cerebral blood flow, but specific intercellular communication mechanisms are unclear. Here we used isolated cerebral arteriole myocytes, astrocytes, and brain slices to investigate whether carbon monoxide (CO) generated by the enzyme heme ox...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.107.164145

    authors: Li A,Xi Q,Umstot ES,Bellner L,Schwartzman ML,Jaggar JH,Leffler CW

    更新日期:2008-02-01 00:00:00

  • Prejunctional inhibition of norepinephrine release caused by acetylcholine in the human saphenous vein.

    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

    authors: Rorie DK,Rusch NJ,Shepherd JT,Vanhoutte PM,Tyce GM

    更新日期:1981-08-01 00:00:00

  • Importance of endogenous angiotensin II in the cardiovascular responses to sympathetic stimulation in conscious rabbits.

    abstract::Pharmacological evidence indicates that angiotensin (Ang II) converting enzyme inhibitors attenuate cardiovascular responses to sympathetic stimulation. To investigate the physiological significance of this attenuation, the pressor and heart rate responses to bilateral carotid occlusion (BCO) were studied before and a...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.66.3.662

    authors: Isaacson JS,Reid IA

    更新日期:1990-03-01 00:00:00

  • Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensin II and phenylephrine.

    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

    authors: Zhang TT,Takimoto K,Stewart AF,Zhu C,Levitan ES

    更新日期:2001-03-16 00:00:00

  • Fcγ receptors and ligands and cardiovascular disease.

    abstract::Fcγ receptors (FcγRs) classically modulate intracellular signaling on binding of the Fc region of IgG in immune response cells. How FcγR and their ligands affect cardiovascular health and disease has been interrogated recently in both preclinical and clinical studies. The stimulation of activating FcγR in endothelial ...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/CIRCRESAHA.116.302795

    authors: Tanigaki K,Sundgren N,Khera A,Vongpatanasin W,Mineo C,Shaul PW

    更新日期:2015-01-16 00:00:00

  • Homozygous missense N629D hERG (KCNH2) potassium channel mutation causes developmental defects in the right ventricle and its outflow tract and embryonic lethality.

    abstract::Loss-of-function mutations in the human ERG1 potassium channel (hERG1) frequently underlie the long QT2 (LQT2) syndrome. The role of the ERG potassium channel in cardiac development was elaborated in an in vivo model of a homozygous, loss-of-function LQT2 syndrome mutation. The hERG N629D mutation was introduced into ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.108.177055

    authors: Teng GQ,Zhao X,Lees-Miller JP,Quinn FR,Li P,Rancourt DE,London B,Cross JC,Duff HJ

    更新日期:2008-12-05 00:00:00

  • Phosphoinositide 3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of deoxycorticosterone acetate-salt hypertensive rats.

    abstract::Arteries from deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-L-arginine (L-NNA) hypertensive but not normotensive rats develop spontaneous tone. LY294002 and wortmannin, phosphoinositide 3-kinase (PI3-kinase) inhibitors, eliminate spontaneous tone. We hypothesized that PI3-kinase protein and/or activity wa...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.0000030861.13850.f1

    authors: Northcott CA,Poy MN,Najjar SM,Watts SW

    更新日期:2002-08-23 00:00:00

  • Evidence for distinct calcium channel agonist and antagonist binding sites in intact cultured embryonic chick ventricular cells.

    abstract::To determine whether calcium channel agonists and antagonists bind to distinct pharmacologically active sites, the binding of dihydropyridine calcium channel agonists and antagonists was related to calcium flux and contractile state in primary monolayer cultures of spontaneously contracting chick embryo ventricular ce...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.60.5.683

    authors: Lee RT,Smith TW,Marsh JD

    更新日期:1987-05-01 00:00:00

  • Store-operated channels mediate Ca(2+) influx and contraction in rat pulmonary artery.

    abstract::Cation channels activated by Ca(2+) store depletion have been proposed to mediate Ca(2+) influx in vascular smooth muscle cells. The aim of this study was to determine if store-operated channels have a functional role in pulmonary artery smooth muscle cells (PASMCs). In intact rat pulmonary artery rings, cyclopiazonic...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/hh2201.100315

    authors: Ng LC,Gurney AM

    更新日期:2001-11-09 00:00:00

  • Length-induced changes in activation during contraction. A study of mechanical oscillations in strontium-mediated contractions of cat and frog heart muscle.

    abstract::The plateau phase of prolonged Sr-mediated contractions of preparations of cat and frog heart muscle was used to study the transient response to abrupt changes in load or length. An oscillatory response (total amplitude equal to or less than 5% Lmax) was obtained. Isotonic oscillations were less damped than their isom...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.38.4.289

    authors: Henderson AH,Cattell MR

    更新日期:1976-04-01 00:00:00

  • Morphometric evidence for non-pressure-related arterial wall thickening in hypertension.

    abstract::To investigate the relation of pressure and vascular wall thickening in hypertension, we coarcted the abdominal aorta upstream to the renal arteries in 14 rats. Sham-coarcted (n = 16) and two-kidney, one-clip (Goldblatt) hypertensive rats (n = 13) served as controls. Tail, femoral, and carotid arterial pressures rose ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.62.5.1001

    authors: Liu JL,Bishop SP,Overbeck HW

    更新日期:1988-05-01 00:00:00

  • From pulsus to pulseless: the saga of cardiac alternans.

    abstract::Computer simulations and nonlinear dynamics have provided invaluable tools for illuminating the underlying mechanisms of cardiac arrhythmias. Here, we review how this approach has led to major insights into the mechanisms of spatially discordant alternans, a key arrhythmogenic factor predisposing the heart to re-entry...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/01.RES.0000224540.97431.f0

    authors: Weiss JN,Karma A,Shiferaw Y,Chen PS,Garfinkel A,Qu Z

    更新日期:2006-05-26 00:00:00

  • Lactate transport in mammalian ventricle. General properties and relation to K+ fluxes.

    abstract::Net cellular L-lactate efflux associated with accelerated anaerobic glycolysis has been implicated as a potential cause of the marked cellular K+ loss contributing to lethal cardiac arrhythmias in ischemic heart and to impaired function of fatigued skeletal muscle. To examine the mechanisms of transsarcolemmal L-lacta...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.74.5.829

    authors: Shieh RC,Goldhaber JI,Stuart JS,Weiss JN

    更新日期:1994-05-01 00:00:00

  • Hypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes.

    abstract::In response to hypoxia and reoxygenation, mammalian cells are known to express a variety of genes to adapt to these external stresses or lead to further cell damage. We investigated the intracellular signaling cascades in cultured rat cardiac myocytes subjected to hypoxia followed by reoxygenation (hypoxia/reoxygenati...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.78.1.82

    authors: Seko Y,Tobe K,Ueki K,Kadowaki T,Yazaki Y

    更新日期:1996-01-01 00:00:00

  • Restoration of resting sarcomere length after uniaxial static strain is regulated by protein kinase Cepsilon and focal adhesion kinase.

    abstract::Physiological or pathological stresses and strains produce longer or wider muscle cells, but resting sarcomere length remains constant. Our goal was to investigate the cellular mechanisms for controlling this optimal, resting sarcomere length. To do so, we cultured neonatal rat cardiomyocytes on microfabricated peg-an...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000121101.32286.C8

    authors: Mansour H,de Tombe PP,Samarel AM,Russell B

    更新日期:2004-03-19 00:00:00

  • Evidence for Ca(2+) activation and inactivation sites on the luminal side of the cardiac ryanodine receptor complex.

    abstract::We have used tryptic digestion to determine whether Ca(2+) can regulate cardiac ryanodine receptor (RyR) channel gating from within the lumen of the sarcoplasmic reticulum (SR) or whether Ca(2+) must first flow through the channel and act via cytosolically located binding sites. Cardiac RyRs were incorporated into bil...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.87.3.201

    authors: Ching LL,Williams AJ,Sitsapesan R

    更新日期:2000-08-04 00:00:00

  • Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure.

    abstract::Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with heart failure induced by 3 to 4 wee...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.78.2.262

    authors: Kääb S,Nuss HB,Chiamvimonvat N,O'Rourke B,Pak PH,Kass DA,Marban E,Tomaselli GF

    更新日期:1996-02-01 00:00:00

  • Molecular composition of 4-aminopyridine-sensitive voltage-gated K(+) channels of vascular smooth muscle.

    abstract::Voltage-gated K(+) channels (Kv) play a critical role in regulating arterial tone by modulating the membrane potential of vascular smooth muscle cells. Our previous work demonstrated that the dominant 4-aminopyridine (4-AP)-sensitive, delayed rectifier Kv current of rabbit portal vein (RPV) myocytes demonstrates simil...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/hh2301.100817

    authors: Thorneloe KS,Chen TT,Kerr PM,Grier EF,Horowitz B,Cole WC,Walsh MP

    更新日期:2001-11-23 00:00:00

  • Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels.

    abstract:RATIONALE:Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings. OBJECTIVE:Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbi...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.111.243790

    authors: Debette S,Visvikis-Siest S,Chen MH,Ndiaye NC,Song C,Destefano A,Safa R,Azimi Nezhad M,Sawyer D,Marteau JB,Xanthakis V,Siest G,Sullivan L,Pfister M,Smith H,Choi SH,Lamont J,Lind L,Yang Q,Fitzgerald P,Ingelsson E,

    更新日期:2011-08-19 00:00:00

  • Unspliced XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction.

    abstract:RATIONALE:Although not fully understood, the phenotypic transition of vascular smooth muscle cells exhibits at the early onset of the pathology of aortic aneurysms. Exploring the key regulators that are responsible for maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) may confer vascular hom...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.117.311450

    authors: Zhao G,Fu Y,Cai Z,Yu F,Gong Z,Dai R,Hu Y,Zeng L,Xu Q,Kong W

    更新日期:2017-12-08 00:00:00

  • Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted.

    abstract::A central role for leukocytes in neointimal hyperplasia after arterial injury is suspected. However, the relative importance of neutrophils and monocytes in balloon or stent-induced injury are not well understood, and mechanistic targeting of leukocyte recruitment or function is crude. We determined the temporal and s...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/hh0402.105956

    authors: Horvath C,Welt FG,Nedelman M,Rao P,Rogers C

    更新日期:2002-03-08 00:00:00

  • Endocardial versus epicardial differences of intracellular free calcium under normal and ischemic conditions in perfused rat hearts.

    abstract::Transmural heterogeneity of myocardial metabolism and function are present in the left ventricle under normal and ischemic conditions. To determine if endocardial versus epicardial differences of [Ca2+]i are also present, perfused rat heart studies using indo-1 fluorescence as an index of [Ca2+]i were performed in the...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.72.5.1082

    authors: Figueredo VM,Brandes R,Weiner MW,Massie BM,Camacho SA

    更新日期:1993-05-01 00:00:00

  • A phosphorus-31 nuclear magnetic resonance study of the metabolic, contractile, and ionic consequences of induced calcium alterations in the isovolumic rat heart.

    abstract::Isolated adult rat hearts perfused in an isovolumic mode were used to study the effects of sodium-potassium pump inhibition and sodium-calcium exchange alterations on the tissue content of adenosine triphosphate, phosphocreatine, inorganic phosphate, and intracellular pH, all measured by phosphorus-31 nuclear magnetic...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.58.4.539

    authors: Hoerter JA,Miceli MV,Renlund DG,Jacobus WE,Gerstenblith G,Lakatta EG

    更新日期:1986-04-01 00:00:00

  • Essential role of bone marrow for microvascular endothelial and metabolic functions in mice.

    abstract:RATIONALE:We have previously demonstrated that the importance of endothelium-derived hyperpolarizing factor (EDHF) increases as the vessel size decreases and that endothelium-derived hydrogen peroxide (H(2)O(2)) is an EDHF in animals and humans, for which endothelial nitric oxide synthase (eNOS) is the major source. Re...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.112.270215

    authors: Nakajima S,Ohashi J,Sawada A,Noda K,Fukumoto Y,Shimokawa H

    更新日期:2012-06-22 00:00:00