INVITED REVIEW

Contributions of cardiomyocytecardiac fibroblastimmunecell interactions in heart failure development

Katsuhito Fujiu Ryozo Nagai

Received: 22 February 2013 / Revised: 13 March 2013 / Accepted: 21 March 2013 / Published online: 6 June 2013

Springer-Verlag Berlin Heidelberg 2013

Abstract The heart contains various types of cells,

including cardiomyocytes, cardiac fibroblasts, many kinds of

immune cells and vascular cells. Initial studies mainly

focused on cardiomyocytes, which directly reflect the con-

tractile function of the heart. Recently, pivotal functions of

cardiac fibroblasts have been revealed in the maintenance of

cardiac function, physiological cardiac remodeling after heart

stress and pathological remodeling using genetically engi-

neered mouse models, like the fibroblast-specific gene

knockout mouse, bone marrow transplantation and immune

cell-specific gene knockout. Moreover, chronic inflammation

is considered to be a basic pathological mechanism that

underlies various diseases, including heart failure. In the

development of heart failure, the contributions of immune

cells like T lymphocytes and monocyte/macrophage lineage

cells have been also reported. Immune cells have diverse and

multiple functions in regulating both pro-inflammatory

effects and the resolution of heart failure. On the one hand,

immune cells have protective effects to compensate for and

overcome heart stresses. On the other hand, they also con-

tribute to sustained inflammation and result in the develop-

ment of heart failure. These observations prompted a shift in

the heart-related studies to include the complex communi-

cations between cardiomyocytes and other kinds of cardiac

cells, including inflammatory cells residing in or recruited to

the heart. This review will summarize the current knowledge

regarding cellcell interactions during cardiac remodeling

and the development of heart failure. We will especially

focus on the interactions among cardiomyocytes, cardiac

fibroblasts and immune cells.

Keywords Cardiac fibroblast Cardiomyocyte Cellcellinteraction Heart failure Immune cell

Introduction

In the heart, cardiac fibroblasts, immune cells and vascular

cells, including vascular endothelial cells and vascular

smooth muscle cells, are all present. Under steady-state

conditions, non-myocytes may exhibit a quiescent pheno-

type, whereas cardiomyocytes are always beating. After the

exposure to heart stress, such as myocardial infarction,

pressure overload, myocarditis, volume overload and so on,

the cardiac fibroblasts change their phenotype to become

activated fibroblasts, which produce growth factors, cyto-

kines, chemokines and extracellular matrix [46]. Simulta-

neously, a variety of immune cells, such as T lymphocytes

and monocyte/macrophage lineage cells infiltrate into the

heart. These T lymphocytes and monocytes/macrophages

have diverse functions, which are regulated in a spatial and

This article is part of the Topical Collection Novel Perspectives on

Heart Failure.

K. Fujiu (&) R. Nagai (&)Department of Cardiovascular Medicine, University of Tokyo,

7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan

e-mail: fujiu-tky@umin.ac.jp

R. Nagai

e-mail: nagai-tky@umin.ac.jp

K. Fujiu

Translational Systems Biology and Medicine Initiative

(TSBMI), the University of Tokyo Graduate School of Medicine,

Tokyo, Japan

R. Nagai

Funding Program for World-Leading Innovative R&D on

Science and Technology (FIRST Program), Tokyo, Japan

R. Nagai

Jichi Medical University, Tochigi, Japan

123

Basic Res Cardiol (2013) 108:357

DOI 10.1007/s00395-013-0357-x

temporal manner [93, 106]. The cellcell interactions

among cardiomyocytes and non-myocytes within the

interstitium of the heart have become an increasingly

popular focus of research on heart failure. These interac-

tions promote adaptive responses against heart stress, and

compensate or overcome these stresses. On the other hand,

these interactions can also provoke pathological remodel-

ing associated with heart diseases, and can thereby result in

heart failure and cardiac death. In this review, we will

present the current knowledge regarding cellcell interac-

tions in the heart after heart stress, such as myocardial

infarction and pressure overload. We will especially focus

on the contribution of cellcell interactions among

cardiomyocytes, cardiac fibroblasts and immune cells to

heart failure.

Cellular components of the heart

Cardiomyocytes, cardiac fibroblasts, endothelial cells,

vascular smooth muscle cells and immune cells are all

major cellular components of the heart. In the 1970s,

efforts to establish the cellular populations of the adult

heart in rats were reported, based on a morphological

analysis using electron microscopy or gradient centrifuga-

tion. Recently, several common cardiac fibroblast markers

have been reported. Discoidin domain receptor 2 (DDR2)

[8] and CD90/thymus cell antigen-1 (Thy1) [42] are cell-

surface markers that can be used for fluorescence-activated

cell sorting (FACS). These discoveries showed that the

adult murine myocardium is composed of 56 % myocytes,

27 % fibroblasts, 7 % endothelial cells and 10 % vascular

smooth muscle cells [8]. Moreover, in the adult rat heart,

the number of cardiomyocytes was 30 %, that of fibroblasts

was 64 % and non-myocyte and non-fibroblast cell popu-

lations made up the remaining 6 %, which includes

immune cells and vascular cells [8]. The approaches using

FACS enabled the analysis of the relative percentages of

distinct, definable cell types present in the developing and

adult heart, as well as the elucidation of the cellcell

communications among various cells within the heart

during the homeostatic state, adaptive response state and

during the development of heart disease.

Cardiomyocytecardiac fibroblast interaction

The important role of cellcell communication between

cardiomyocytes and cardiac fibroblasts in both develop-

ment and/or cardiovascular diseases was implied by an

initial in vitro study using conditioned media or a simpli-

fied co-culture system [25]. For example, murine cardio-

myocytes developed a hypertrophied phenotype when they

were co-cultured with cardiac fibroblasts or their condi-

tioned media supplemented with interleukin (IL)-6. In that

report, the IL-6 signaling in cardiomyocytes in co-culture

with cardiac fibroblasts was suggested to be key in pro-

moting cardiomyocyte hypertrophy [31]. In addition to

IL-6, the tumor necrosis factor (TNF)a production was alsoupregulated by cardiomyocytes when they were co-cul-

tured with cardiac fibroblasts [9]. These results from co-

culture systems suggested that paracrine factors are one of

the method by which cardiomyocytes and cardiac fibro-

blasts communicate. However, forced physical disconnec-

tion between cardiomyocytes and cardiac fibroblast using

an antibody for a cardiac fibroblast plasma membrane

protein or connexin 43 inhibited cell adhesion and

decreased the IL-6 production, but did not decrease the

TNFa production [9]. These results highlighted theimportance of direct cellcell interactions between

cardiomyocytes and cardiac fibroblasts, in addition to the

existence of multiple non-physical communication path-

ways mediated by cytokine production, during the devel-

opment of cardiac hypertrophy (Fig. 1). In addition to

cardiomyocyte hypertrophy, a recent in vitro study sug-

gested that cardiac fibroblasts also affected the contractile

activity [59] and electrophysiological conditions of the

cardiomyocytes [77]. These results suggested that cardiac

fibroblasts may have pivotal pathological roles via their

interactions with cardiomyocytes in vivo. Many studies

have shown that cardiac fibroblasts were activated by heart

stresses and that they became proliferative and secreted

cytokines and growth factors and eventually differentiated

into cardiac myofibroblasts, which expressed smooth

muscle a-actin. There are a wide variety of heart stresses,including mechanical stress, hypoxia [76], immune cell-

derived inflammatory cytokines [107] and augmented

neurohormonal stimulation [64].

Among these stresses, the reninangiotensin system and

b-adrenergic stimulation have been extensively investi-gated. Cardiac fibroblasts were found to express the

angiotensin II receptor [99] and b-adrenergic receptors[100] and these receptors were involved in the pathological

process of heart diseases due to enhanced reninangioten-

sinaldosterone signaling [35, 82, 84] and chronic

b-adrenergic overstimulation [73]. These two signalingpathways have been established as standard targets for the

treatment of heart failure. Recently, the interdependence

between angiotensin II receptor 1 and the serotonin

receptor [5-HT(2B)] in cardiac fibroblasts was reported

[44]. These two receptors in cardiac fibroblasts affected the

sympathetic overstimulation-dependent heart failure, thus

suggesting that 5-HT(2B) might be a novel therapeutic

target for adrenergic overstimulation-dependent heart fail-

ure [44]. In addition to these signaling pathways, nuclear

factor kappa-light-chain-enhancer of activated B cells

Page 2 of 15 Basic Res Cardiol (2013) 108:357

123

(NF-jB) [5, 53], the Smad signaling pathway[38], mitogenactivated protein kinase [72] and phosphoinositide 3-kinase

(PI3K) [15] were also suggested to be involved in cardiac

fibroblast activation during the development of heart fail-

ure, and might also be candidate therapeutic targets.

Cyclic nucleotide phosphodiesterase 1A (PDE1A) is a

key regulator of cardiac fibroblast activation induced by

angiotensin II and TGF-b through the Ca2?/calmodulinpathway both in vitro and in vivo [71].

The extracellular heterodimeric protein S100A8/A9 is

produced in fibroblasts and macrophages in the heart fol-

lowing myocardial ischemia [104]. The production of

S100A8/A9 leads to increases in the activity of nuclear

factor (NF)-jB and the expression of proinflammatorycytokines in cardiac fibroblasts and macrophages [104].

S100A8/A9 recruits macrophages into the heart by acti-

vating the receptor of advanced glycation end-products

(RAGE) on macrophage [104]. Secreted S100A8/A9

affects cardiomyocytes by activating MAP kinases JNK,

ERK1/2 and NF-jB, which mediates signals downstreamof RAGE following ischemic heart failure and results in a

reduced cardiac function [104].

The TNF receptor superfamily member fibroblast

growth factor-inducible molecule 14 (Fn14) is produced

from cardiac fibroblasts in response to endothelin-1 stim-

ulated by right ventricular pressure overload [74]. Fn14

activates and leads to the proliferation of cardiac fibroblast

cells autonomously, results in collagen synthesis via RhoA-

dependent nuclear translocation of myocardin-related

transcription factor-A (MRTF-A)/MAL [74].

In just the past decade, more details about the cellcell

interactions between cardiomyocytes and cardiac fibro-

blasts have been revealed by genetically manipulated mice

using the Cre-loxP system and estrogen receptor-inducible

system. This technique enabled the generation of cardio-

myocyte-specific [4, 39] and fibroblast-specific [45]

IL-6 family IL-6 family

GP130 GP130

cardiomyocyte cardiac fibroblast

JAK MAPK PI3K

hypertrophy cell death

iNOS

SERCAPLBRYR

contraction

extracellularmatrix

production

migrationproliferation

XONADPH

superoxideNO

peroxynitrite

Connexin43

IL-6 production

Stressinduced AngIIproduction

AngIIAT1

Fibroblast activation

AngIIIL-6 family

Fig. 1 Interleukin-6 family regulates the heart remodeling bymodulating cardiomyocytes and cardiac fibroblasts. Current knowl-

edge of cellular molecular mechanisms is shown. In cardiomyocytes,

IL-6 induces cardiac hypertrophy via JAK signaling, cardiomyocyte

death via MAPK and inducible nitric oxide synthase, xanthine

oxidase and NADPH oxidase expression through their receptor

GP130. Induced superoxide and nitric oxide produce peroxynitrite.

Peroxynitrite decreases contractility through its effects on SERCA2a,

ryanodine receptor and phospholamban. In cardiac fibroblasts, IL-6

induces activation of extracellular matrix production and migration

and proliferation of cardiac fibroblasts. Cardiac stresses induce

angiotensin II production from cardiac fibroblasts and secreted

angiotensin II induces IL-6 production of cardiomyocytes. IL

interleukin, JAK Janus Kinase, MAPK mitogen activated protein

kinase, PI3K Phosphoinositide 3 kinase, SERCA Sarcoplasmic

reticulum calcium ATPase, XO xanthine oxidase, PLB phospholam-

ban, iNOS inducible nitric oxide synthase, RYR ryanodine receptor,

AngII angiotensin II, AT1 angiotensin II receptor type 1, IL-6 family

IL-6 leukemia inhibitory factor and cardiotropin-1

Basic Res Cardiol (2013) 108:357 Page 3 of 15

123

knockout or overexpression mice, and allowed the analysis

of cell type-specific functions in vivo. Haploinsufficiency

of a transcription factor, Klf5, inhibited cardiac hypertro-

phy and cardiac fibrosis after angiotensin II infusion or

pressure overload [86, 94]. However, cardiomyocyte-spe-

cific Klf5 knockout mice did not show any reduction of the

cardiac hypertrophy and fibrosis after left ventricular

pressure overload. On the other hand, fibroblast-specific

Klf5 knockout mice showed significantly suppressed car-

diac hypertrophy and fibrosis [94]. However, the fibroblast-

specific Klf5 knockout mice subsequently developed severe

heart failure, because of a truncation of the adaptive car-

diac response against pressure overload, including cardiac

hypertrophy and fibrosis, which resulted in heart failure

and cardiac death (Fig. 2).

Placental growth factor (Pgf) is another key regulator

of the interaction between cardiomyocytes and cardiac

fibroblasts. Pgf knockout mice died of severe heart failure

within a week after pressure overload [1]. Reductions of

fibroblast activation and angiogenesis after pressure

overload were observed. In contrast, the overexpression

PGF in cardiomyocytes augmented the cardiac hypertro-

phy in response to pressure overload [1]. Because the PGF

receptor is expressed in cardiac fibroblasts, but not in

cardiomyocytes, the PGF secreted from cardiomyocytes

only affects non-cardiomyocytes (mainly cardiac fibro-

blasts) and promoted cardiac adaptive responses after

pressure overload. Ras-associated domain family 1 iso-

form A (Rassf1a), a tumor suppressor gene, was reported

to enhance the secretion of TNFa by cardiac fibroblasts,and this secreted TNFa facilitates the increases of thecardiac hypertrophy and cardiac fibroblast proliferation

[20]. These reports also suggested that cardiac hypertro-

phy and cardiac fibrosis are part of an appropriate adap-

tive response, and that the loss of these adaptive responses

clearly resulted in a poor prognosis. Although cardiac

hypertrophy and cardiac fibrosis can be both a positive

and negative response to the physiological conditions, the

differences in the survival rates after heart stress in

genetically manipulated mice strongly support the

importance of these responses in the protection against

heart stress.

KLF5

IGF-1PDGF-A

KLF5 KLF5

Wild type cardiac fibroblast specific Klf5knockout mouse

a

b

pressure overloadangiotensin II infusion

cardiac hypertrophycardiac fibrosis

adaptive responsetruncation of adaptive responseby Klf5 deficiency in cardiac fibroblasts

htaeddnaeruliaftraehevila

pressure overload

Fig. 2 Cardiac fibroblasts facilitate adaptive responses againstcardiac pressure overload. a In cardiac fibroblasts, transcriptionfactor Kruppel-like factor 5 induces insulin-like growth factor 1 and

platelet-derived growth factor A chain after pressure overload. IGF1

is required for induced cardiac remodeling including cardiac hyper-

trophy and cardiac fibrosis after pressure overload and angiotensin II

infusion. b Although in wild-type mice, cardiac hypertrophy and

cardiac fibrosis are observed after pressure overload, this stress is

compensated by these appropriate responses and all mice can survive.

Cardiac fibroblast-specific Kruppel-like factor 5 knock mice develop

heart failure and show high mortality by lack of these adaptive

responses. KLF5 Kruppel-like factor 5, IGF1 insulin-like growth

factor 1, PDGF-A platelet-derived growth factor A chain

Page 4 of 15 Basic Res Cardiol (2013) 108:357

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Cardiomyocytes and neuronal/vascular cell interactions

The sympathetic nervous system controls cardiac contrac-

tility, heart rate and cardiac hypertrophy through interac-

tion of neurons and cardiomyocytes by norepinephrine

secretion [109]. In neurons, angiotensin II induces and

nitric oxide inhibits sympathetic activation and norepi-

nephrine release [119]. In experimental models, ablation of

sympathetic nerves results in reduced cardiomyocytes size

[113]. These effects are mediated by the ubiquitin protea-

some followed by activation of autophagy. This atrophic

remodeling is caused by the reduction of basal stimulation

of adrenergic b2-receptors [113] and can be mimicked byneuron-specific angiotensin converting enzyme 2 overex-

pression in mice which have lower norepinephrine levels.

The reduction of sympathetic activity protects against

cardiac hypertrophy induced by angiotensin II infusion

[27]. These results suggest that sympathetic neuroncar-

diomyocyte interactions induced by norepinephrine pro-

duction are required for the regulation of the

cardiomyocyte volume in maintenance and pathological

remodeling.

In terms of inflammation, vascular endothelial cells also

contribute to heart failure development by expressing cell

adhesion molecules. Cell adhesion molecules, including

selectins, integrins and the immunoglobulin gene super-

family of adhesion receptors, provoke leukocyte migration

from blood vessels into the cardiac interstitium [34].

Endothelial cell dysfunction via reduction of nitric oxide

production induces the expression of intercellular adhesion

molecule-1 (ICAM-1) and vascular cell adhesion mole-

cules-1 (VCAM-1). These cell adhesion molecules induce

the interaction of leukocytes with endothelial cells and

result in the accumulation of leukocytes; infiltrating leu-

kocytes provoke the interaction of immune cells, cardio-

myocytes and fibroblast via the actions of proinflammatory

cytokines.

Blood vessels supply oxygen for cardiac contraction. In

response to pressure overload, cardiomyocytes produce

VEGF and induce angiogenesis, thus adapting supply to the

increased oxygen demand of hypertrophic cardiomyocytes.

In later stages, p53 inhibits VEGF production from

cardiomyocytes and reduced oxygen supply contributes to

reduced contractile function and heart failure [83].

Contribution of inflammation in heart failure

development

The levels of many cytokines, chemokines and growth

factors were observed to be augmented during the adaptive

responses against heart stress and the development of heart

failure. These factors induce phenotypic changes in steady-

state cardiomyocytes and quiescent cardiac fibroblasts to

generate the active form of these cells, i.e. abundant

cytokine-producing cardiomyocytes and cardiac fibro-

blasts. Consequently, the increased paracrine factors from

these two kinds of cells can recruit immune cells and

provoke acute inflammatory changes. Recruited inflam-

matory cells from the bone marrow and spleen interact with

cardiomyocytes and cardiac fibroblasts, and make more

complex inflammatory statuses [46]. An acute response

that includes the infiltration of immune cells, like granu-

locytes and inflammatory monocytes/macrophages, into the

heart and the increased vascular permeability mainly exerts

favorable effects on the heart suffering from stresses and

injury, and enhances the cardiac repair, wound healing,

adaptive cardiac hypertrophy, etc. Supporting this idea, the

inhibition of acute inflammatory cell infiltration into the

heart by depletion of CC chemokine receptor 5 or intra-

venous injections of clodronate-containing liposomes

worsened the cardiac remodeling and healing after myo-

cardial infarction in model mice [102, 114]. However,

chronic inflammation has recently been reported to be a

common mechanism underlying many kinds of lifestyle-

related diseases, including coronary heart disease, diabetes

mellitus and cancer. Serum markers of inflammation, such

as the sustained elevation of inflammatory cytokines and

growth factors, in heart failure patients also augmented and

reflected the severity of their heart failure and clinical

outcomes [81, 97].

In chronic inflammation, macrophages undergo polari-

zation and contribute to tissue injury. In myocardial

infarction, classically activated macrophages produce pro-

inflammatory cytokines (M1 macrophages), and alterna-

tively activated macrophages (M2) anti-inflammatory

cytokines; both, are increased in the heart. Class A scav-

enger receptor (SRA) knockout mice have a reduction of

infiltrated M2 macrophages and increased M1 macro-

phages that result in exacerbation of the cardiac dysfunc-

tion and fibrosis following myocardial infarction [41]. A

particular importance of SRA for the M2 phenotype

polarization has been reported [41].

Bone marrow cells-derived mesenchymal stromal cells

(MSCs) also contribute to repair through their anti-

inflammatory effects. MSCs infiltrate into the heart fol-

lowing myocardial infarction and secrete interleukin-10,

which mediates a switch from an inflammatory monocyte/

macrophage lineage to anti-inflammatory lineages [41].

Regulatory T-cells are also suggested to contribute to

M2 polarization following myocardial infarction via IL-10

production [95].

In this context, the communication among immune cells,

cardiomyocytes and cardiac fibroblasts in the interstitium

of the heart leads to the formation of an immunoregulatory

network, and chronic inflammation might occur if these

Basic Res Cardiol (2013) 108:357 Page 5 of 15

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cells fail to switch off their inflammatory programs, which

might lead to the inappropriate survival and retention of

leukocytes [11].

Intercellular mediators control cellcell interactions

Intercellular mediators produced by immune cells, cardio-

myocytes and cardiac fibroblasts are key factors in the

complex mechanism of connection among the different

types of cells, and have provided new therapeutic targets

for heart failure. In fact, during the development of heart

failure, large numbers of pro-inflammatory mediators are

secreted and contribute to the cellular dysfunction, modu-

late cellcell interactions, affect numerous signaling path-

ways and the cross-talk among signaling pathways [65].

Below, we describe the best-characterized mediators by

which immune cells, cardiomyocytes and cardiac fibro-

blasts interact during the development of heart failure and/

or the progression of other heart diseases.

Interleukins

Interleukins are a group of cytokines which are mainly

produced by immune cells, like T cells and monocyte/

macrophage lineage cells, as well as cardiomyocytes, car-

diac fibroblasts and vascular endothelial cells. IL-6 and its

signal transducer, a 130-kDa glycoprotein (gp130; CD130)

is expressed in cardiomyocytes and cardiac fibroblasts, and

is associated with cardiac hypertrophy and cardiac fibrosis

[30] (Fig. 1). IL-6 is upregulated in the heart after myo-

cardial infarction [14, 22, 47]. The angiotensin II secreted

from cardiac fibroblasts also induced IL-6 production from

the cardiomyocytes, and an AT-1 receptor antagonist

inhibited cardiomyocyte hypertrophy and fibroblast pro-

liferation [30]. These results suggested that the IL-6 pro-

duction in cardiomyocytes contributes significantly to

cardiomyocyte hypertrophy by an autocrine pathway and to

cardiac fibroblast proliferation by a paracrine pathway.

Angiotensin II can induce various members of the IL-6

family, including IL-6, leukemia inhibitory factor and

cardiotropin-1, in cardiac fibroblasts [82]. These IL-6

family members induce significant hypertrophy of cardio-

myocytes through gp130 [82]. The administration of a

neutralizing antibody against IL-6 or gp130 (CD130)

resulted in the reduction of hypertrophic gene expression.

IL-6 blockade also led to reduced cardiac fibroblast pro-

liferation. Signal transducer and activator of transcription 3

(STAT3) is a key signal transducer that acts downstream of

gp130 in both cardiomyocytes and cardiac fibroblasts [28,

118]. Gp130 and STAT3 phosphorylation are altered in

end-stage dilated cardiomyopathy patients [79]. The

induction of signaling via the gp130STAT3 axis provoked

unfavorable downstream activation of this critical pathway

during heart failure [40]. The IL-6 family and gp130 axis is

the most extensively analyzed signal transduction pathway

between cardiomyocytes and cardiac fibroblasts in terms of

the effects on cardiac hypertrophy and cardiac fibrosis.

IL-1b and its receptor, the type I IL-1 receptor (IL-1RI), are also markedly induced in the infarcted heart,

and this signaling is essential for the activation of the

fibrogenic pathways in the healing heart [12]. IL-1bleads to extra cellular matrix remodeling by inducing the

migration of cardiac fibroblasts [72] and matrix

metalloproteinase production [87], which promotes car-

diac dilatation and cardiac rupture. IL-1b also inducescardiac dysfunction through nitric oxide production [85],

modifying b-adrenergic signaling [37] and via a reduc-tion of phospholamban [70]. On the other hand, IL-1RI

knockout mice showed decreased infiltration of neutro-

phils and macrophages into the myocardium after

ischemia/reperfusion injury [12]. Mice lacking the IL-1

receptor also showed a reduction of myofibroblast acti-

vation and collagen deposition, but no reduction of the

infarct size [12]. These results suggest that IL-1 signal-

ing regulates pathogenic cardiac remodeling in both

cardiomyocytes and cardiac fibroblasts.

IL-17, a recently identified cytokine, is released from

Th17 cells, which are a subset of CD4 effector T cells. IL-

17 is also induced in the infarct area after myocardial

infarction, and depletion of IL-17 by genetic deficiency or

a neutralizing antibody resulted in a reduction of the infarct

size and preserved cardiac function [7, 63]. The mecha-

nisms underlying these effects of IL-17 are suggested to be

due to the fact that IL-17 provokes the apoptosis of

cardiomyocytes and induces chemokines that mediate

neutrophil migration [63]. In addition to Th17 cells, recent

in vitro studies suggested that cardiac fibroblasts can pro-

duce IL-17 and provoke collagen and metalloproteinase 1

production through the IL-17 receptor expressed on the

cardiac fibroblasts [16, 103]. These results imply that IL-17

is a key mediator linking Th17 cells, cardiac fibroblasts and

cardiomyocytes that contributes to pathological

remodeling.

IL-10 is a general anti-inflammatory cytokine that is

also induced after cardiac reperfusion injury or heart

failure in a canine model [29] and in humans [108].

Elevated IL-10 is considered to antagonize the effects of

pro-inflammatory cytokines like TNFa [51]. A studydemonstrated that IL-10 reduced the oxidative stress and

TNFa-induced apoptosis of cardiomyocytes in vitro, andthe administration of IL-10 after myocardial infarction led

to a reduction of the inflammatory cell invasion and

inflammatory cytokine production and resulted in an

ameliorated infarct area and cardiac remodeling [23].

These results suggest that IL-10 has important roles in the

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adaptive response during myocardial infarction and heart

failure by affecting both cardiomyocytes and cardiac

fibroblasts.

TNFa

Tumor necrosis factor is a cytokine involved in inflam-

mation that is recognized by its receptors, TNF receptor

type I (TNF-R1) and TNF-R2 [53]. The serum level of

TNFa is elevated in heart failure patients in a mannercorresponding to the severity of the heart failure [60].

TNFa provokes various effects on TNF-R expressing tis-sues, including the myocardium [98], through the MAPK

and/or NF-jB pathways. Pathological conditions likehemodynamic pressure overloading or myocardial infarc-

tion induce TNFa production in both cardiomyocytes andnon-cardiomyocytes [18, 43, 49]. TNFa induced the pro-liferation of cardiac fibroblasts and collagen deposition,

increasing the matrix metalloproteinase activity and

inflammatory cytokine production from cardiac fibroblasts,

and also induced the apoptosis of cardiomyocytes and

resulted in cardiac dysfunction and heart failure [91]. As

expected based on these findings, Tnf knockout mice

showed a reduction of cardiac death, infarct size, myo-

cardial apoptosis, inflammatory cell infiltration, inflam-

matory cytokine production, MMP activity and deposition

of extracellular matrix after myocardial infarction [91].

Phosphatase and tensin homolog deleted on chromo-

some ten (PTEN) inactivates protein kinase Akt and pro-

motes cell death in the heart [75]. PTEN is also induced in

the heart following myocardial infarction, while PTEN

heterozygous knockout mice show a reduction of the

number of infiltrated immune cells in the heart and a pre-

served cardiac function following myocardial infarction

[75]. In PTEN heterozygous knockout mice, the production

of TNFa and MMP-2 is decreased and the production ofIL-10 is increased in the heart following myocardial

infarction [75]. In addition, inhibition of IL-10 receptors

increases TNFa and MMP-2 production following myo-cardial infarction [75]. PTEN is also important in remote

ischemic preconditioning (RIPC) [13]. PTEN is inactivated

in limb muscles following lower limb RIPC. The inacti-

vation of PTEN promotes STAT3 phosphorylation and

induces IL-10 production in limb muscles. The IL-10

released from ischemic skeletal muscles activates protec-

tive signaling pathways in the heart [13]. These results

suggest that PTEN is critically involved in the post-myo-

cardial infarction remodeling induced by TNFa via theAkt/IL-10 signaling pathway.

TNFa directly impairs the contractility of cardiomyo-cytes through sphingosine, a metabolite stimulated by

TNFa binding, by decreasing the intracellular calciumrelease and inotropic activity [32, 96], inhibiting the

cardiac L-type calcium channel current and contractile

calcium transients [55], reducing the SERCA2A expression

and activity [48] and reducing the b-adrenergic respon-siveness [37]. In addition, TNFa can directly induce car-diomyocyte hypertrophy [110] and apoptosis [56]. These

findings indicate that TNFa might be a key to the devel-opment of heart failure and could be a therapeutic target for

heart failure. Indeed, several preclinical studies showed

promising data that indicated favorable results for a TNFablocking strategy against heart failure. In an animal model

of myocardial infarction, TNFa also had ambivalentfunctions [88]. Indeed, clinical trials of anti-TNFa therapyusing the soluble TNFa selective antagonist, etanercept, forNew York Heart Association class II to IV chronic heart

failure patients (ejection fraction B 30 %) were terminated

prematurely due to a lack of benefit. A subanalysis of these

studies concluded that the outcome of patients after the

administration of etanercept was worsened compared to

patients who did not receive the drug [66]. These results

implied that the TNFa signaling in cardiomyocytes andnon-cardiomyocytes in patients with heart failure is more

complex than was previously thought. Moreover, the

intervention targeting this single molecule associated with

inflammation and heart failure did not bring about favor-

able effects, thus suggesting that chronic inflammation

after heart stress may actually be a favorable adaptive

response, and that excessive blockade of the inflammatory

responses during heart failure might lead to decompensa-

tion. More cell type-specific analyses of this signaling

pathway under different conditions will be required.

Transforming growth factor-b

Transforming growth factor b (TGF-b) is expressed incardiac fibroblasts, cardiomyocytes and vascular cells, and

is induced in the myocardium by myocardial infarction and

heart failure [19, 21]. Classical TGF-b signaling occurs viabinding to the TGF-b type 2 receptor and activation of theTGF-b type I receptor. Thereafter, both a Smad-dependentpathway and non-canonical pathway (Smad-independent)

are activated. In the non-canonical pathway, PDE1A-

mediated cardiac fibroblast activation and cardiac fibrosis

in response to TGFb have recently been reported [71]. Inthis report, PDE1A has a pivotal function in the develop-

ment of fibrosis induced by both TGFb and angiotensin II[71]. Blockade of the classical TGF-b signaling usingsystemic Smad3 knockout in mice led to their development

of severe hypertrophy and less fibrosis after left ventricular

pressure overload [24]. On the other hand, cardiomyocyte-

specific forced non-canonical TGF-b activation by over-expression of TGF-b activated kinase 1 (TAK1) alsoinduced cardiac hypertrophy and heart failure in mice

[117]. A left ventricular pressure overload mouse model

Basic Res Cardiol (2013) 108:357 Page 7 of 15

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treated with a TGF-b signal neutralizing antibody resultedin suppression of the classical pathway (Smad) activation

in the interstitium (non-cardiomyocytes), but not in

cardiomyocytes, and the non-canonical activation (TAK1

activation) was also not affected. Although the cardiac

fibrosis was markedly suppressed, the cardiac dysfunction

was not ameliorated in this mouse model [54]. These

results based on systemic knockout mice and systemic

protein blockade methods have limitations for analyzing

the mechanism(s) underlying complex cellcell interac-

tions, because the same gene may work differentially in

different kinds of cells. A cell type-specific analysis of

TGF-b signaling will be necessary to better understand therole of the molecule in heart failure.

In response to this need, cardiomyocyte-specific TGF-breceptor knockout mice were recently reported [54]. These

mice showed reduced cardiac hypertrophy and cardiac

fibrosis as a result of the inhibited cardiomyocyte and

interstitial Smad and TAK1 activation [54] (Fig. 3). Inter-

estingly, the non-Smad pathways in cardiomyocytes,

including the Ras-MEK, Rho GTP-ase, phosphoinositide-3-

kinase and TAK1 pathways, might be the predominant

pathways leading to cardiac hypertrophy and cardiac dys-

function, because cardiomyocyte-specific Smad4 knockout

mice exhibit hypertrophy and heart failure [105] and Smad3

knockout worsens the hypertrophic response to pressure

overload [24]. Among the non-Smad pathways, TAK1 can

phosphorylate P38-MAPK, which promotes cardiac dys-

function [62]. In cardiomyocytes, connective tissue growth

factor and bone morphogenetic protein 7 are key paracrine

factors connecting these cells to cardiac fibroblasts in

response to TGF-b signaling [54]. Connecting tissue growthfactor is thought to promote myofibroblast activation and to

affect cardiomyocyte dysfunction, in addition to Smad

signaling in the development of cardiac fibrosis, hypertro-

phy and myocarditis [36, 54, 68, 111]. Bone morphogenetic

protein 7 was also shown to suppress TGF-b-mediatedcardiac fibrosis and the epithelial mesenchymal transition

[116]. TGF-b1 stimulation can suppress bone morphoge-netic protein 7 by a TAK1-dependent pathway [54]. The

non-Smad pathway in cardiomyocytes is becoming gradu-

ally recognized to have a major role in TGF-b signaling,especially in the communication between cardiomyocytes

and cardiac fibroblasts, in terms of heart failure.

Insulin-like growth factor

Insulin-like growth factor-1 (IGF1) is expressed in cardiac

fibroblasts and promotes cardiac cardiomyocyte hypertro-

phy through phosphoinositide 3-kinase signaling [69].

IGF1 is a downstream target of KLF5 that is activated by

KLF5 after pressure overload [94] (Fig. 2). The adminis-

tration of an IGF-1 inhibitor to wild-type mice with

pressure overload also led to the development of severe

heart failure [94]. These results clearly show that KLF5-

IGF-1 signaling in cardiac fibroblasts, but not in cardio-

myocytes, is required for adaptive responses, like cardiac

hypertrophy and cardiac fibrosis, during pressure overload.

Natriuretic peptide

The serum levels of atrial natriuretic peptide (ANP) and

brain natriuretic peptide (BNP) are clinically used as

diagnostic markers which reflect volume overload in heart

failure and the therapeutic index of heart failure treatment.

Mice that were genetically deficient in the common

receptor for these two peptides, guanylyl cyclase-A,

showed marked cardiac hypertrophy and fibrosis, suggest-

ing that ANP and BNP have protective effects against

cardiac hypertrophy and fibrosis [52]. ANP and BNP are

produced by cardiomyocytes, and BNP directly affects and

protects cardiomyocytes following myocardial infarction

by opening ATP-sensitive potassium (KATP) channel [17].

BNP also directly affects cardiac fibroblasts and limits

TGF-b-mediated gene expression associated with cardiacfibrosis and cardiac fibroblast proliferation [50]. In addi-

tion, ANP reduces the endothelin-1 expression, which can

exert proliferative effects on cardiac fibroblasts in vitro

[33]. These data suggest that these two peptides from

cardiomyocytes antagonize the fibrogenic activity of car-

diac fibroblasts in a paracrine fashion.

Immune cells and cardiomyocytes/cardiac fibroblasts

interactions

Several kinds of immune cells proliferate or infiltrate into

the heart after cardiac stress, and are considered to promote

cardiac remodeling. Monocytes (Ly-6Chigh at acute phase

and Ly-6Clow at late phage) and macrophages are one of

the major immune cell types that accumulate in the heart

during stress, such as myocardial infarction or heart failure.

The origin of cardiac macrophages is believed to be from

bone marrow-derived monocytes, which differentiate into

macrophages in the heart, or may be the result of the

proliferation of resident macrophages within the heart.

Recently, splenic monocytes were reported to function as a

reservoir of Ly-6C high-inflammatory monocytes that

participate in the repair of heart disease in the acute phase

[92]. In addition, this rapid deployment of inflammatory

monocytes from the spleen depends on angiotensin sig-

naling [92].

Monocyte chemotactic protein-1 (MCP-1) is a major

chemokine that recruits inflammatory monocytes into var-

ious tissues. In a pressure overload model, MCP-1 was

upregulated in the early stage of heart remodeling. Chronic

Page 8 of 15 Basic Res Cardiol (2013) 108:357

123

treatment using a neutralizing antibody against MCP-1

inhibited the inflammatory monocyte/macrophage infiltra-

tion and cardiac fibroblast proliferation. This treatment

attenuated cardiac fibrosis through the inhibition of TGF-binduction, and ameliorated the left ventricular diastolic

dysfunction, but not the cardiomyocyte hypertrophy [57].

These results suggest that MCP-1 mediates the accumula-

tion of monocyte/macrophage lineage cells into the heart,

and that this promotes myocardial fibrosis and diastolic

dysfunction in the pressure overloaded heart through a

TGF-b-mediated process.The reninangiotensinaldosterone system is associated

with cardiac remodeling, and a competitive antagonist of

aldosterone (spironolactone) or a mineral corticoid-specific

inhibitor (eplerenone) has been indicated for reducing the

risk of cardiac death in patients with heart failure and

myocardial infarction. Myeloid cell-specific mineralocor-

ticoid receptor knockout mice showed a lack of classical

activation of infiltrated macrophages into the heart after

angiotensin II infusion, and the infiltrated macrophages

exhibited alternative activation profiles [101]. These mice

exhibited reduced cardiac hypertrophy and fibrosis, sug-

gesting that the mineralocorticoid receptor in cardiac

macrophages is critical for cardiac macrophage polarity

(pro-classical activation), cardiac hypertrophy and cardiac

fibrosis [101].

On the other hand, monocyte/macrophage depletion by

clodronate liposome administration, which can damage or

deplete monocytes and macrophages via their phagocytic

activity, resulted in exacerbated left ventricular ejection

function in a hypertensive heart disease model [115].

Monocyte/macrophage lineage cell depletion in hyperten-

sive hearts led to the abundant infiltration of inflammatory

cells within areas of cardiomyocyte loss, predominantly

CD4? T lymphocytes [115]. These results imply that

monocytes/macrophages have protective effects on adap-

tive stress through inhibiting T cell infiltration into the

heart. Monocytes/macrophages have diverse and bivalent

TGF-TGF- type I receptor

cardiomyocyte cardiac fibroblast

Smad dependentpathway

non Smad pathway

hypertrophy contraction

extracellularmatrix

production

myofibroblast activation

dominant

Smad3, Smad4

suppressor

no effect

TAK1Ras-MEKRho GTPasePI3K

P38MAPK

CTGF

BMP7

TGF- type I receptor

TGF-

fibrosis

suppress

Fig. 3 TGF-b signaling in cardiomyocytes and cardiac fibroblasts.TGF-b signaling is associated with hypertrophy of cardiomyocyte andcardiac fibrosis revealed by recent works are shown. In cardiomyo-

cytes, TGF-b induces hypertrophy through TGF-b type I receptor.TGF-b type I receptor transduces its signals after cardiac stressesmainly through non-Smad pathways. For example, TGF-beta acti-

vated kinase 1 (TAK1) induces hypertrophy of cardiomyocytes and

reduces cardiac contractility via P38MAPK. In addition, TAK1

activation inhibits bone morphogenetic protein 7 (BMP7) production

that can inhibit myofibroblast activation. Smad 4 might inhibit cardiac

hypertrophy under TGF-b signaling. In cardiac fibroblasts, TGF-bsignaling provokes myofibroblast activation through TGF-b type Ireceptor and promotes cardiac fibrosis. TAK1 activation in cardio-

myocytes also produced connective tissue growth factor (CTGF).

CTGF reduces contractility of cardiomyocytes and inhibits myofi-

broblast activation. TGF-b transforming growth factor beta, TAK1TGF-beta activated kinase 1, MEK MAPK/ERK kinase, Rho GTPase

Rho guanosine triphosphate, PI3K phosphoinositide-3-kinase, BMP7

bone morphogenetic protein 7, CTGF connective tissue growth factor

Basic Res Cardiol (2013) 108:357 Page 9 of 15

123

effects on tissue remodeling after heart stress. More sub-

type analyses of monocytes/macrophages should be per-

formed in the future to better understand their roles. The

balances of pro-inflammatory monocytes/macrophages

versus alternatively activated monocytes/macrophages in

the heart at every time point after heart stress might have

complex effects on cardiomyocyte and cardiac fibroblast

phenotypic modulation and activation.

Mast cells are also key effector cells during allergic

reactions, and show immune responses resulting from the

degranulation of synthesized bioactive agents, like

growth factors, cytokines and other molecules. Mast cells

are also increased during cardiac hypertrophy and heart

failure in humans [90]. These cells secrete platelet-

derived growth factor A, TGF-b, TNF-a and histamine,and affect the cardiac function. Mast cell stabilizing

drugs ameliorated heart failure via reduced cardiac

remodeling in a volume overload model [10]. In addi-

tion, after pressure overload in a mouse model, the

infiltrated mast cells induced platelet-derived growth

factor A chain synthesis and promoted the proliferation

and collagen synthesis of cardiac fibroblasts. This mast

cellcardiac fibroblast interaction is required for atrial

fibrosis and affects the susceptibility to atrial fibrillation,

which is the most common type of arrhythmia occurring

in heart failure [61]. These results suggest that cardiac

mast cells have a key role in the regulation of atrial

myocardial remodeling and in the communication

between cardiomyocytes and cardiac fibroblasts. In

addition to platelet-derived growth factor A chain, it has

recently been reported that angiotensin II-induced Rac 1

activation leads to atrial remodeling and atrial fibrillation

via the CTGF and lysyl oxidase-mediated miR-21

expression [2].

To date, several T cell subsets have been reported.

CD4? T cells are divided into four subtypes, including

helper T cells (Th1, Th2), Th17 cells and regulatory T

cells (Tregs). T cells are also suggested to contribute to

cardiac remodeling via cellcell interactions, as well as

the production of cytokines and growth factors. In gen-

eral, Th1 cells secrete Th1 cytokines like interferon-c,and promote an anti-fibrogenic response, while Th2

cytokines, like IL-4,-5 and -13, promote fibrosis [67]. In

the early stage of inflammation, Th1 cytokines are

secreted to eradicate intracellular pathogens. In the late

phase of inflammation, Th2 cytokines enhance chronic

inflammation, leading to the elimination of extracellular

organisms and contributing to the development of

chronic inflammatory diseases. The administration of

N(G)-nitro-L-arginine methyl ester (L-NAME: NO syn-

thesis inhibitor) to mice can induce hypertension. Dif-

ferent strains of mice, including C57BL/6 SCID mice,

which lack T and B lymphocytes, C57BL/6 wild-type

mice and BALB/c mice subjected to L-NAME-induced

hypertension showed different Th1/Th2 polarity, i.e. null,

Th1 polarity and Th2 polarity, respectively, whereas all

of the strains showed the same degree of hypertension.

The hypertension-induced cardiac fibrosis is decreased in

SCID mice, unchanged in C57BL/6 wild-type mice and

significantly increased in BALB/c mice [112]. Another

hypertension model (an angiotensin II continuous infu-

sion model) showed severe left ventricular dilatation,

thinning and fibrosis in BALB/c mice, but not in C57BL/

6 mice, whereas the same degree of hypertrophied

cardiomyocytes was observed in both BALB/c and

C57BL/6 mice [78]. These results suggest that Th1 cells

and cytokines might initiate fibroblastic activity, and that

Th2 cells and cytokines might contribute to the late or

chronic stage of fibrosis.

IL-17- and IL-22-producing CD4? cells, called Th17

cells, play an important role in promoting inflammation

during tissue remodeling. IL-17 can induce or functionally

augment inflammatory cytokines, including IL-6, IL-1band TNFa, and can promote extracellular matrix remod-eling by producing matrix metalloproteinases or inhibiting

repair components, like proteoglycans [3]. IL-17 is a

pleiotropic cytokine that can modulate other cytokine

functions in multiple ways. Among them, the post-tran-

scriptional modification of IL-17 can stabilize the mRNA

of many cytokines through AU-rich elements in the 30UTR,a common feature of inflammatory cytokine genes [80]. IL-

17 blockade using an anti-IL-17 antibody resulted in

decreased cardiac fibrosis in an isoproterenol-infusion rat

heart failure model [26]. In this model, the MMP-1 and

receptor activator of nuclear factor-rB ligand (RANKL)expression and collagen synthesis were inhibited, and the

levels of tissue inhibitor of metalloproteinases and osteo-

protegerin (OPG) were increased in cardiac fibroblasts

[26]. These results indicate that Th17 cells control cardiac

fibrosis by the IL-17-RANKL/OPG system and MMP

production in cardiac fibroblasts, or via the stabilization of

pro-inflammatory cytokines mRNA in various cardiac

cells and immune cells.

Tregs are an anti-inflammatory lineage of CD4? T

lymphocytes that express FoxP3 and produce anti-

inflammatory cytokines/growth factors, such as IL-10

and/or TGF-b. In a heart disease model, CD4?CD25?

Tregs were increased by angiotensin II infusion and

myocardial infarction, and adoptive transfer of Tregs led

to a reduction of cardiac hypertrophy, anti-inflammatory

and anti-fibrotic effects and resulted in a preserved car-

diac function via IL-10 production and a direct cellcell

interaction [58, 95]. These results suggested that there is

a close relationship among Tregs, cardiomyocytes and

cardiac fibroblasts, and confirms their importance in

cardiac remodeling.

Page 10 of 15 Basic Res Cardiol (2013) 108:357

123

Natural killer T cells (NKT cells)

NKT cells have been shown to be involved in inflammation

and tissue remodeling. The infiltration of NKT cells was

increased in the non-infarct area of the left ventricle after

myocardial infarction in mice [89]. Moreover, the admin-

istration of a NKT cell activator, a-galactosylceramide(aGC) in a mouse myocardial infarction model, led toenhanced infiltration of NKT cells in the non-infarcted

area. The left ventricular dilatation and mortality due to

heart failure were significantly attenuated in the aGCadministration group [89]. It was suggested that these

effects are dependent on NKT cells, because NKT deficient

mice did not show these effects, and because IL-10 is the

most potent effector cytokine for this process [89]. NKT

cells play a protective role after myocardial infarction and

heart failure via IL-10 production.

Dendritic cells

Dendritic cells infiltrate in the infarct heart. Depletion of

bone marrow-derived dendritic cell using CD11c-diphteria

toxin receptor transgenic mice showed deteriorated left

ventricular function and remodeling after myocardial

infarction model. The dendritic cells ablation group

exhibited long-lasting inflammatory cytokines like IL-1b,IL-18 and TNFa. In addition, anti-inflammatory cellsincluding Ly-6Clow monocytes and alternatively activated

macrophages were significantly infiltrated in the hearts of

dendritic cell depleted group [6]. These results suggest that

cardiac dendritic cells have a potent immunoprotective

function after myocardial infarction.

Concluding remarks

Recent heart failure research has been focused not only on

cardiomyocytes, but also on non-myocytes, which have

been recognized as quiescent and structural cells under

normal conditions. Unveiling the pivotal functions of non-

myocytes has demonstrated that they have dynamic and

diverse functions during tissue remodeling as an adaptive

response and during the development of heart failure. In

this review, we summarized the recent reports of the cell

cell interactions in the heart. However, there is room for

further research into the cellcell interactions under both

physiological and pathological conditions in the heart.

Importantly, immune cells are mainly derived from non-

heart organs, like the bone marrow, spleen, thymus and

intestinal organs. Moreover, the recruitment of these

immune cells is at least partly controlled by the brain via

neurotransmitters or humoral proteins. In the next decade,

research should focus on further elucidating the mecha-

nisms of heart failure in terms of cellcell interactions and

organorgan communication.

Acknowledgments This study was supported by the FundingProgram for World-Leading Innovative R&D on Science and Tech-

nology (FIRST Program) (to R.N.), Grants-in-Aid for Scientific

Research (S) and (B), and Grants-in-Aid for Young Scientists

(B) from JSPS (23390203, 22229006, 23790835) (to R.N., K.F.); a

grant for Translational Systems Biology and Medicine Initiative (to

R.N.) from JST.

Conflict of interest On behalf of all authors, the correspondingauthor states that there is no conflict of interest.

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