Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 244

CA ANP

BNP

neuroregulin
EGF
IGF1

ET1

FGF TGF TNF

ATn2

stress

FGFR RTK TGFR TNFR

GPCR

GC

Ras
Rac Rho

PLC

MAP4K
MAP3K

NIK

PI3K

TAK1

cGMP

ROS

DAG

PP3 Raf MAP3K

IKK

PDK1

IP3

PKG

MAP2K4/ 7 MAP2K3/6 MAP2K1/ 2 MAP2K5

PKC

Ca

PKB

JNK p38 ERK1/2 ERK5

PKD

Cam

JNKPase

GSK3

mTOR

NFAT

CamK

NFκΒ

cFlIP

antioxydants

transcription factors

nucleus

NFAT

HDAC

Fig. 5.13 Signaling pathways that initiate the cardiac hypertrophy (Source: [ 411 ]). Signaling
starts at the sarcolemma by ligands (natriuretic peptides ANP and BNP, angiotensin-2 [ATn2],
endothelin-1 [ET1], fibroblast growth factor [FGF], epidermal growth factor [EGF], insulin-
like growth factor-1 [IGF1], transforming growth factor- α

[TNF]) that bind to receptors (G-protein-coupled receptors [GPCR] and receptor Tyr kinases
[RTK]), activating cytosolic effectors (guanylate cyclase-A [GC]; protein kinases [PKB, PKC,
PKD, and PKG]; phospholipases [PLA2 and PLC]; mitogen-activated protein kinase pathways
[MAP4K, MAP3K, Raf, MAP2K, ERK, JNK, and P38MAPK]; small GTPases [Ras, Rac, and
Rho]; diacylglycerol [DAG] and inositol trisphosphate [IP 3 ]; phosphatidylinositol 3-kinase [PI3K];
phosphoinositide-dependent kinase [PDK]; glycogen synthase kinase-3

β [TGF], and tumor-necrosis factor-

[GSK3]; calmodulin-
dependent kinase [CamK]; target of rapamycin [TOR]; nuclear factor of activated T-cells [NFAT];
NF κ B-inducing kinase [NIK]; inhibitor of NF κ B kinase [IKK]; and cyclin-dependent kinase), then
transcription factors (nuclear factor- κ B[NF κ B], and nuclear factor of activated T-cells [NFAT]),
and nuclear components (histone deacetylases [HDAC]). NF κ B impedes prolonged JNK signaling
induced by TNF α via anti-oxidants and cellular flice-inhibitory protein (cFlIP), thus subsequent
apoptosis. Transient MAPK stimulation by TNF α favors cell growth.

β

Catecholamines, angiotensin-2, and endothelin-1 bind to specific G-protein-
coupled receptors (

1-adrenoceptor and angiotensin-2 and endothelin receptors) of
the cardiomyocyte sarcolemma (Fig. 5.13 )[ 411 ].

α