Neuregulin-1/erbB activities with focus on the susceptibility of the heart to anthracyclines

Table 1 Biological effects of neuregulin-1/erbB in embryonic and postnatal cardiomyocytes

Experimental system	Monitored response	Intracellular signal	Ref.
Cultured cells
NRG1 administration in neonatal cardiomyocytes	Sarcomeric F-actin polymerization	PI 3’-kinase	[16]
	Myofibrillogenesis - Growth	Ras-Mek-erk1/2	[17]
	Proliferation	PI 3’-kinase	[17]
	NOS activation		[42]
	Muscarinic activation		[43]
	Karyo- cytokinesis		[44]
NRG1 administration in human ESC	Specification of cardiomyocytes of the conduction lineage		[45]
Animal models
NRG1b injection to ex vivo developing E12.5 dpc mouse	Differentiation of trabeculae		[17]
	DNA synthesis, Proliferation	PI 3’-kinase	[17]
NRG1 administration in mouse with heart failure	Improved cardiac performance		[40]
Hypomorphic NRG1 deficiency in E8.5dpc mouse	Destabilization of gene regulatory network in the left ventricle	Erk1/2	[39]
Mouse ventricular-erbB2-KO	Overt dilation and reduced survival in erbb2 F/- postnatal mouse		[31]
Mouse ventricular-erbB2-KO	Dilation with cellular apoptosis		[32]
Mouse ventricular-erbB4-KO	Overt ventricular dilation at 3 mo and reduced survival		[33]
Lapatinib inhibition of erbB1/erbB2 in Mouse	erbB2-physiologic hypertrophy in pregnancy	MEK1/erk1/2	[34]
Adult ventricular-erbB4-KO	Cell division in myocardial infarction		[44]

Summary of cardiac activities of neuregulin-1 (NRG1)-erbB2/erbB4 signaling inferred from in vitro system and animal model studies. The NRG1 activities, -proliferation, myofibrillogenesis, ventricular remodeling, and repair-, were assessed based on the outcomes of the exogenous administration of NRG1 or by the complete or partial loss of erbB2/erbB4 signaling. NOS: Nitric oxide synthase; MEK1: Mitogen activated kinase erk kinase 1; ESC: Embryonic stem cells.

Table 2 Biological effects of combined neuregulin-1/erbB signaling and anthracyclines

Experimental system	Monitored response	Ref.
Cultured cardiomyocytes
NRG-1 administration	Prevented myofibril disarray	[55]
	Attenuated troponin degradation	[56]
Animal models
NRG1-deficiency/doxorubicin (NRG1 heterozygous mouse)	Induced heart failure	[57]
NRG1-deficiency/doxorubicin (Ventricular specific-erbB4-KO)	Deregulated Protein Homeostasis Autophagic vacuolization	[58]

Summary of effects mediated by anthracycline-induced toxicity and by neuregulin-1 (NRG1)-erbB2/erbB4 signaling in in vitro system and animal models. The NRG-1 activities on cardiomyocyte survival, myofibril organization and ventricular homeostasis were assessed based on the exogenous administration of NRG1 or by the outcome of an impaired signaling as discussed throughout the article.

Table 3 Cardiac phenotypic modifications

Morphology	WT	KO	WTD	KOD
Young adult (1 mo)
Heart/body weight (mg/g)	5.2 ± 0.4	5.3 ± 0.6	5.2 ± 0.5	6.2 ± 0.8a
Body weight (g)	17.4 ± 2.0	17.3 ± 2.2	17.3 ± 2.0	17.2 ± 1.5
Adult (3 mo)
Heart/body weight (mg/g)	5.6 ± 0.6	7.0 ± 0.8d	5.4 ± 0.7	6.7 ± 0.8d
Body weight (g)	30.1 ± 2.5	30.3 ± 2.2	29.4 ± 2.2	28.4 ± 2.2
Cardiotoxic gene groups
Dilation (ratio)	-	3	1.8	2.8
Hypertrophy (ratio)	-	9.9	3.3	6.5
Damage (ratio)	-	3.7	3.7	3.6
Cell death/ necrosis (Ratio)	-	3.0	4.3	3.1
Measured activity
Caspase 3 (arbitrary units)	0.25 ± 0.17	0.44 ± 0.17	0.84 ± 0.09a	0.35 ± 0.07
Autophagic vacuolization (n°)	0.07 ± 0.1	0.35 ± 0.3	0.2 ± 0.2	2.4 ± 2.1a
Serum cTnI (mg/mL)	0.15 ± 0.1	3.6 ± 1.5	0.7 ± 0.2	14.5 ± 4.2a
LVDP (mmHg)	109.2 ± 7.1	42 ± 8.2a	94.5 ± 5.5	31.5 ± 5.4a
Tau ½	37.4 ± 1.9	38.1 ± 4.9	36.1 ± 3.1	34.6 ± 2.9

Morphological and biochemical modifications studied in the aggravated cardiotoxic condition of the doxorubicin-treated-ventricular specific erbB4-KO mouse model. Summary of hypertrophic-associated morphological changes determined in mouse at the age of 1 and 3 mo, group of differentially expressed genes clustered into a wide-range of cardiotoxic conditions, biochemical activities associated to cell death and of physiological systolic and diastolic parameters are represented as discussed in the text.

^aP < 0.05 vs WT,

^dP < 0.01 vs WT and WTD. WTD: Doxorubicin-treated wildtype; KOD: Doxorubicin-treated erbB4-KO; WT: Treated wildtype.