TABLE 1.

A summary of selected studies highlighting the beneficial role of EGFR signaling in the heart.

Role of EGFR	Study model	Intervention	Results	Refs.
ErbB1 expression protects from myocardial I/R injury	Myocyte-specific Hif2a or ErbB1 knockout mice		• RNA-binding protein 4 suppression attenuated hypoxia-inducible factor 2A-dependent induction of ErbB1	(Lee et al., 2020)
			• ErbB1 myosin Cre + mice suffered larger infarctions and could not be saved by amphiregulin
EGF protects against myocardial I/R injury	C57BL/6 (B6) mice	EGF	• EGF inhibits ROS and H2O2 induced cell death and by Nrf2 activation	Ma and Jin, (2019)
			• EGF limited cardiac I/R injury and apoptosis in vivo
NRG-1 receptor ErbB3 limits apoptosis and improves cell survival	Wistar rats	I/R injury and protective post-conditioning procedure	• ErbB3 expression increased after I/R injury (with and without post-conditioning)	Morano et al. (2017)
			• ErbB3 expression improved cell survival and reduced mitochondrial dysfunction and apoptosis
NRG-1β induces proliferation, survival and paracrine signaling	Primary human cardiac ventricular fibroblasts	NRG-1β	• NRG-1β improved proliferation and survival of human cardiac fibroblasts by inducing ErbB3-dependent activation of ErbB2	Kirabo et al. (2017)
NRG-1 inhibits ER stress and protects against myocardial I/R injury	Sprague-dawley and wistar rats	NRG-1 ligand of cardiomyocyte ErbB receptors	• NRG-1 reduced cardiomyocyte ER stress, hypoxia-reoxygenation induced apoptosis and myocardial infarct size induced by I/R injury	Fang et al. (2017)
ErbB activation alleviates doxorubicin induced cardiac toxicity	Stem cell derived human cardiac myocytes	Trastuzumab and lapatinib	• ErbB activation with NRG protected against doxorubicin-induced cardiac myocyte injury, while inhibition with trastuzumab exacerbated it	Eldridge et al. (2014)
EGFR/ErbB2 improves T1D hearts recovery from I/R injury	Wistar rat	AG825 or AG1478	• Chronic AG1478 or AG825 treatment decreased cardiac recovery in normal and diabetic rats	Akhtar et al. (2012b)
		EGF and/or losartan	• Acute EGF treatment pre or post ischemia improved cardiac recovery and opposed ischemic changes by EGFR/ErbB2 activation in T1D hearts
EGFR protects myocytes in reperfused hearts	C57/Bl6 mice	AG1478, GM6001, or CRM197	• EGFR inhibition limited CCPA-mediated functional protection in reperfused hearts	Williams-Pritchard et al. (2011)
EGFR maintains normal cardiac function and left ventricular thickness	C57BL/6J (B6) mice	EGFR small molecule TKIs, irreversible EKB-569 and reversible AG1478	• EGFR inhibition resulted in left ventricular thickness and cardiac function changes via increasing fibrosis and altering left ventricular apoptotic gene expression	Barrick et al. (2008)
ErbB4 plays a major role in normal cardiac conduction and ventricular trabeculation	ErbB4 cardiac-knockout mice		• ErbB4 deletion resulted in severe dilated cardiomyopathy, abnormal conduction, impaired ventricular trabeculation and premature death	Garcia-Rivello et al. (2005)
EGFR/ErbB1 activation protects against stress-induced cardiac injury	Adult Swiss-CD1 male mice	EGF, AG1478	• EGF led to lower increase in total LDH, LDH-1, and creatinine kinase activity, and protected against stress-induced cardiac injury (these effects were abolished by simultaneous AG1478 administration)	Pareja et al. (2003)
ErbB2 prevents dilated cardiomyopathy	C57BL/6J mice		• Ventricular-restricted ErbB2 deletion resulted in dilated cardiomyopathy with impaired left ventricular contractility and increased susceptibility of cardiomyocytes to anthracycline toxicity	Crone et al. (2002)

I/R, ischemia/reperfusion; NRG, neuregulin; ER, endoplasmic reticulum; T1D, type-1 diabetes; CCPA, 2-chloro-N(6)-cyclopentyladenosine; CK, creatinine kinase.