Increased sarcoplasmic reticulum calcium leak but unaltered contractility by acute CaMKII overexpression in isolated rabbit cardiac myocytes.

Abstract:

:The predominant cardiac Ca2+/calmodulin-dependent protein kinase (CaMK) is CaMKIIdelta. Here we acutely overexpress CaMKIIdeltaC using adenovirus-mediated gene transfer in adult rabbit ventricular myocytes. This circumvents confounding adaptive effects in CaMKIIdeltaC transgenic mice. CaMKIIdeltaC protein expression and activation state (autophosphorylation) were increased 5- to 6-fold. Basal twitch contraction amplitude and kinetics (1 Hz) were not changed in CaMKIIdeltaC versus LacZ expressing myocytes. However, the contraction-frequency relationship was more negative, frequency-dependent acceleration of relaxation was enhanced (tau(0.5Hz)/tau(3Hz)=2.14+/-0.10 versus 1.87+/-0.10), and peak Ca2+ current (ICa) was increased by 31% (-7.1+/-0.5 versus -5.4+/-0.5 pA/pF, P<0.05). Ca2+ transient amplitude was not significantly reduced (-27%, P=0.22), despite dramatically reduced sarcoplasmic reticulum (SR) Ca2+ content (41%; P<0.05). Thus fractional SR Ca2+ release was increased by 60% (P<0.05). Diastolic SR Ca2+ leak assessed by Ca2+ spark frequency (normalized to SR Ca2+ load) was increased by 88% in CaMKIIdeltaC versus LacZ myocytes (P<0.05; in an multiplicity-of-infection-dependent manner), an effect blocked by CaMKII inhibitors KN-93 and autocamtide-2-related inhibitory peptide. This enhanced SR Ca2+ leak may explain reduced SR Ca2+ content, despite measured levels of SR Ca2+-ATPase and Na+/Ca2+ exchange expression and function being unaltered. Ryanodine receptor (RyR) phosphorylation in CaMKIIdeltaC myocytes was increased at both Ser2809 and Ser2815, but FKBP12.6 coimmunoprecipitation with RyR was unaltered. This shows for the first time that acute CaMKIIdeltaC overexpression alters RyR function, leading to enhanced SR Ca2+ leak and reduced SR Ca2+ content but without reducing twitch contraction and Ca2+ transients. We conclude that this is attributable to concomitant enhancement of fractional SR Ca2+ release in CaMKIIdeltaC myocytes (ie, CaMKII-dependent enhancement of RyR Ca2+ sensitivity during diastole and systole) and increased ICa.

journal_name

Circ Res

journal_title

Circulation research

authors

Kohlhaas M,Zhang T,Seidler T,Zibrova D,Dybkova N,Steen A,Wagner S,Chen L,Brown JH,Bers DM,Maier LS

doi

10.1161/01.RES.0000200739.90811.9f

subject

Has Abstract

pub_date

2006-02-03 00:00:00

pages

235-44

issue

2

eissn

0009-7330

issn

1524-4571

pii

01.RES.0000200739.90811.9f

journal_volume

98

pub_type

杂志文章
  • Activation of natural killer T cells ameliorates postinfarct cardiac remodeling and failure in mice.

    abstract:RATIONALE:Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies ha...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.112.270132

    authors: Sobirin MA,Kinugawa S,Takahashi M,Fukushima A,Homma T,Ono T,Hirabayashi K,Suga T,Azalia P,Takada S,Taniguchi M,Nakayama T,Ishimori N,Iwabuchi K,Tsutsui H

    更新日期:2012-09-28 00:00:00

  • Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction.

    abstract::To investigate the functional consequences of a tropomyosin (TM) mutation associated with familial hypertrophic cardiomyopathy (FHC), we generated transgenic mice that express mutant alpha-TM in the adult heart. The missense mutation, which results in the substitution of asparagine for aspartic acid at amino acid posi...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.85.1.47

    authors: Muthuchamy M,Pieples K,Rethinasamy P,Hoit B,Grupp IL,Boivin GP,Wolska B,Evans C,Solaro RJ,Wieczorek DF

    更新日期:1999-07-09 00:00:00

  • Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling.

    abstract:RATIONALE:Transcatheter, intramyocardial injections of bone marrow-derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. OBJECTIVE:We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothes...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.111.242610

    authors: Williams AR,Trachtenberg B,Velazquez DL,McNiece I,Altman P,Rouy D,Mendizabal AM,Pattany PM,Lopera GA,Fishman J,Zambrano JP,Heldman AW,Hare JM

    更新日期:2011-04-01 00:00:00

  • Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions.

    abstract::Atherosclerotic lesion development seems to be inflammatory in nature and involves the recruitment of monocytes to the vessel wall. In this study, we investigated the role of vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) connecting segment-1 containing the amino acid sequence ILDV as functional ligan...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.87.2.153

    authors: Huo Y,Hafezi-Moghadam A,Ley K

    更新日期:2000-07-21 00:00:00

  • Cardiac Stem Cell Hybrids Enhance Myocardial Repair.

    abstract:RATIONALE:Dual cell transplantation of cardiac progenitor cells (CPCs) and mesenchymal stem cells (MSCs) after infarction improves myocardial repair and performance in large animal models relative to delivery of either cell population. OBJECTIVE:To demonstrate that CardioChimeras (CCs) formed by fusion between CPCs an...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.115.306838

    authors: Quijada P,Salunga HT,Hariharan N,Cubillo JD,El-Sayed FG,Moshref M,Bala KM,Emathinger JM,De La Torre A,Ormachea L,Alvarez R Jr,Gude NA,Sussman MA

    更新日期:2015-09-25 00:00:00

  • Protective Effects of Activated Myofibroblasts in the Pressure-Overloaded Myocardium Are Mediated Through Smad-Dependent Activation of a Matrix-Preserving Program.

    abstract:RATIONALE:The heart contains abundant interstitial and perivascular fibroblasts. Traditional views suggest that, under conditions of mechanical stress, cytokines, growth factors, and neurohumoral mediators stimulate fibroblast activation, inducing ECM (extracellular matrix) protein synthesis and promoting fibrosis and ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.118.314438

    authors: Russo I,Cavalera M,Huang S,Su Y,Hanna A,Chen B,Shinde AV,Conway SJ,Graff J,Frangogiannis NG

    更新日期:2019-04-12 00:00:00

  • Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type 1 by endothelial injury.

    abstract::Accumulation of plasminogen activator inhibitor type 1 (PAI-1) in the arterial wall may accelerate atherogenesis by inhibiting fibrinolysis, diminishing proteolysis of extracellular matrix proteins, or modifying migration of vascular smooth muscle cells. Increased intramural expression of the PAI-1 gene is induced by ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.73.4.671

    authors: Sawa H,Sobel BE,Fujii S

    更新日期:1993-10-01 00:00:00

  • Electrophysiology and ultrastructure of canine subendocardial Purkinje cells isolated from control and 24-hour infarcted hearts.

    abstract::Ventricular arrhythmias that accompany myocardial infarction in dogs may be secondary to the altered electrophysiological properties of the subendocardial Purkinje fibers that survive 24 hours after the coronary occlusion. To better understand the ionic mechanisms that underlie the altered electrical activity of these...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.65.4.955

    authors: Boyden PA,Albala A,Dresdner KP Jr

    更新日期:1989-10-01 00:00:00

  • Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance.

    abstract::We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine beta-synthase-/apolipoprotein E-deficient (CBS(-/-)/apoE(-/-)) mice. We o...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000242559.42077.22

    authors: Liao D,Tan H,Hui R,Li Z,Jiang X,Gaubatz J,Yang F,Durante W,Chan L,Schafer AI,Pownall HJ,Yang X,Wang H

    更新日期:2006-09-15 00:00:00

  • Acute depletion of endothelial β3-integrin transiently inhibits tumor growth and angiogenesis in mice.

    abstract:RATIONALE:The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against α...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.114.301591

    authors: Steri V,Ellison TS,Gontarczyk AM,Weilbaecher K,Schneider JG,Edwards D,Fruttiger M,Hodivala-Dilke KM,Robinson SD

    更新日期:2014-01-03 00:00:00

  • Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKCepsilon translocation.

    abstract::Protein kinase C (PKC) is a key mediator of many diverse physiological and pathological responses. Although little is known about the specific in vivo roles of the various cardiac PKC isozymes, activation-induced translocation of PKC is believed to be the primary determinant of isozyme-specific functions. Recently, we...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.86.11.1173

    authors: Mochly-Rosen D,Wu G,Hahn H,Osinska H,Liron T,Lorenz JN,Yatani A,Robbins J,Dorn GW 2nd

    更新日期:2000-06-09 00:00:00

  • Ca(2+) signaling in cardiac myocytes overexpressing the alpha(1) subunit of L-type Ca(2+) channel.

    abstract::Voltage-gated L-type Ca(2+) channels (LCCs) provide Ca(2+) ingress into cardiac myocytes and play a key role in intracellular Ca(2+) homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca(2+) signaling in ventricular myocytes from 4-month-old transg...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/hh0202.103230

    authors: Song LS,Guia A,Muth JN,Rubio M,Wang SQ,Xiao RP,Josephson IR,Lakatta EG,Schwartz A,Cheng H

    更新日期:2002-02-08 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

  • Direct visualization of lipid deposition and reverse lipid transport in a perfused artery : roles of VLDL and HDL.

    abstract::The major goal of this study was to determine the interactions of VLDL surface and core lipids with the artery wall. We first demonstrated in vitro that surface lipid in VLDL could be traced using the phospholipid-like fluorescent probe 1,1'-dioctadecyl-3,3, 3',3'-tetramethyl-indocarbocyanine (DiI). The core of VLDL p...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.86.7.768

    authors: Rutledge JC,Mullick AE,Gardner G,Goldberg IJ

    更新日期:2000-04-14 00:00:00

  • Delayed end ejection increases isovolumic ventricular relaxation rate in isolated perfused canine hearts.

    abstract::We sought to determine the ejection variables that are principally responsible for increases in isovolumic ventricular relaxation rate observed with increases in stroke volume. In nine isolated canine hearts, left ventricular ejection was controlled by patterns specially designed to isolate the ejection parameters mos...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.68.1.300

    authors: Hori M,Kitakaze M,Ishida Y,Fukunami M,Kitabatake A,Inoue M,Kamada T,Yue DT

    更新日期:1991-01-01 00:00:00

  • Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo.

    abstract::Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization,...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000133247.69803.c3

    authors: van Weel V,Deckers MM,Grimbergen JM,van Leuven KJ,Lardenoye JH,Schlingemann RO,van Nieuw Amerongen GP,van Bockel JH,van Hinsbergh VW,Quax PH

    更新日期:2004-07-09 00:00:00

  • Attenuation of the exercise pressor reflex. Effect of opioid agonist on substance P release in L-7 dorsal horn of cats.

    abstract::Using alpha-chloralose-anesthetized cats, we studied blood pressure and heart rate responses to static contraction and passive stretch of the triceps surae muscle before and after microdialyzing the mu-opioid agonist [D-Ala2]-methionine enkephalinamide (DAME, 200 mumol/L) into the L-7 dorsal horn of the spinal cord. I...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.77.2.326

    authors: Meintjes AF,Nóbrega AC,Fuchs IE,Ally A,Wilson LB

    更新日期:1995-08-01 00:00:00

  • Novel biological functions of high-density lipoprotein cholesterol.

    abstract::In addition to its role in reverse cholesterol transport, high-density lipoprotein (HDL) cholesterol has direct action on numerous cell types that influence cardiovascular and metabolic health. Cellular responses to HDL entail its capacity to invoke cholesterol efflux that causes signal initiation via scavenger recept...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/CIRCRESAHA.111.258673

    authors: Mineo C,Shaul PW

    更新日期:2012-09-28 00:00:00

  • Bone morphogenetic protein signaling modulates myocardin transactivation of cardiac genes.

    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

    authors: Callis TE,Cao D,Wang DZ

    更新日期:2005-11-11 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

  • The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction.

    abstract:RATIONALE:The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Mo...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.119.316007

    authors: Pan B,Li J,Parajuli N,Tian Z,Wu P,Lewno MT,Zou J,Wang W,Bedford L,Mayer RJ,Fang J,Liu J,Cui T,Su H,Wang X

    更新日期:2020-07-31 00:00:00

  • Analysis of systolic bulging. Mechanical characteristics of acutely ischemic myocardium in the conscious dog.

    abstract::To determine the mechanical factors affecting regional segmental motion after acute coronary occlusion, we studied seven conscious dogs, instrumented with sonomicrometers. Loading conditions were changed by the withdrawal of 500 ml of blood and the transfusion of 800 ml of blood. To express segmental motion, percent s...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.58.2.209

    authors: Akaishi M,Weintraub WS,Schneider RM,Klein LW,Agarwal JB,Helfant RH

    更新日期:1986-02-01 00:00:00

  • Medical Therapy for Heart Failure Associated With Pulmonary Hypertension.

    abstract::The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction. 1 This success has coincided with the stepwise availability of drugs that target neurohormonal activation: β-adrenergic receptor blockers (β-blockers), ACE (angiotensin-convertin...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/CIRCRESAHA.118.313650

    authors: Zelt JGE,Chaudhary KR,Cadete VJ,Mielniczuk LM,Stewart DJ

    更新日期:2019-05-24 00:00:00

  • Is there a serotonin-induced hypertensive coronary chemoreflex in the nonhuman primate?

    abstract::The purpose of this study was to investigate the nature of the serotonin-induced coronary chemoreflex in the conscious monkey. Ten chronically prepared and four acute monkeys were used in this study. Five chronically prepared animals had catheters in the left atrium, ascending aorta, descending aorta, and, bilaterally...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.52.3.312

    authors: Cornish KG,Zucker IH

    更新日期:1983-03-01 00:00:00

  • Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo.

    abstract::Muscle ring finger (MuRF) proteins have been implicated in transmitting mechanical forces to cell signaling pathways through their interactions with the giant protein titin. Recent evidence has linked mechanically-induced stimuli with the control of serum response factor activity and localization through MuRF2. This o...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000259559.48597.32

    authors: Willis MS,Ike C,Li L,Wang DZ,Glass DJ,Patterson C

    更新日期:2007-03-02 00:00:00

  • Spread of contraction in rabbit ear artery preparations in response to stimulation by norepinephrine.

    abstract::To investigate the spread of contraction in the rabbit ear artery, changes in segment diameter were measured after local stimulation. No spread of contraction was produced by direct current or local application of norepinephrine (NE). Repetitive electrical stimulation caused contraction which spread far from the point...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.49.3.600

    authors: Vonderlage M

    更新日期:1981-09-01 00:00:00

  • Left ventricular and myocardial function in mice expressing constitutively pseudophosphorylated cardiac troponin I.

    abstract:RATIONALE:Protein kinase (PK)C-induced phosphorylation of cardiac troponin (cTn)I has been shown to regulate cardiac contraction. OBJECTIVE:Characterize functional effects of increased PKC-induced cTnI phosphorylation and identify underlying mechanisms using a transgenic mouse model (cTnI(PKC-P)) expressing mutant cTn...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.109.205427

    authors: Kirk JA,MacGowan GA,Evans C,Smith SH,Warren CM,Mamidi R,Chandra M,Stewart AF,Solaro RJ,Shroff SG

    更新日期:2009-12-04 00:00:00

  • Innate and adaptive immunity in the pathogenesis of atherosclerosis.

    abstract::This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive ...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/01.res.0000029784.15893.10

    authors: Hansson GK,Libby P,Schönbeck U,Yan ZQ

    更新日期:2002-08-23 00:00:00

  • Protein synthesis and degradation during starvation-induced cardiac atrophy in rabbits.

    abstract::To determine the relative importance of protein degradation in the development of starvation-induced cardiac atrophy, in vivo fractional synthetic rates of total cardiac protein, myosin heavy chain, actin, light chain 1, and light chain 2 were measured in fed and fasted rabbits by continuous infusion of [3H] leucine. ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.60.6.933

    authors: Samarel AM,Parmacek MS,Magid NM,Decker RS,Lesch M

    更新日期:1987-06-01 00:00:00

  • Novel pharmacophores of connexin43 based on the "RXP" series of Cx43-binding peptides.

    abstract::Gap junction pharmacology is a nascent field. Previous studies have identified molecules that enhance intercellular communication, and may offer potential for innovative antiarrhythmic therapy. However, their specific molecular target(s) and mechanism(s) of action remain unknown. Previously, we identified a 34-aa pept...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.109.200576

    authors: Verma V,Larsen BD,Coombs W,Lin X,Spagnol G,Sorgen PL,Taffet SM,Delmar M

    更新日期:2009-07-17 00:00:00