TABLE 2.

A summary of selected in vivo studies highlighting the detrimental role of EGFR/ErbB signaling in the heart.

Role of EGFR	Study model	Intervention	Results	Refs.
Amphiregulin via EGFR activation increases cardiac fibrosis after myocardial infarction	C57BL6 mice	Amphiregulin and gefitinib	• Amphiregulin, via EGFR activation, promoted cardiac fibroblast migration, proliferation, and collagen synthesis (gefitinib abrogated all these effects)	Liu et al. (2020)
			• Amphiregulin deletion improved cardiac function and increased survival rate
EGFR contribute to myocardial infarction in T2D	T2D mice (db−/db−)	Group 1: Untreated	• EGFR and ER stress inhibitors reduced the cell apoptosis, inflammation, and myocardial infarct size in T2D mice after myocardial I/R injury induction	Mali et al. (2018)
		Group 2: AG1478
		Group 3: Tudca
EGFR plays a role cardiac fibrosis	C57Bl/6J mice	Generation of osteoglycin-null mice (OGN-/-)	• OGN, via EGFR inhibition, negatively regulated cardiac fibrosis by attenuating myofibroblast proliferation and migration	Zuo et al. (2018)
		Ang II infusion	• Chronic Ang II infusion in OGN deficient mice increased cardiac fibrosis and impaired cardiac function
EGFR increases cardiac remodeling in diabetic cardiomyopathy	C57/BL6 mice	Gefitinib and ramipril	• Gefitinib, via EGFR inhibition, prevented lipid peroxidation, antioxidant enzymes damage, myocardial hypertrophy, myocardial damage and improved Ca2+ homeostasis in STZ-induced cardiomyopathy	Shah et al. (2018)
EGFR induces cardiac hypertrophy	C57BL/6 mice	AG1478, 542 and 54	• AG1478, 542 and 543, via EGFR inhibition, attenuated ang II- and EGF-induced cardiac hypertrophy	Peng et al. (2016)
EGFR contributes to cardiac inflammation and injury associated with high fiber diet	Apo-E knockout mice	AG1478 and 542	• EGFR inhibitors attenuated palmitic acid and hyperlipidemia-induced cardiac injury and inflammation in mice fed with high fat	(Li et al., 2016)
EGFR role in cardiac damage and remodeling through oxidative stress	STZ-induced T1D mice	AG1478 and 451	• AG1478 and 451, via EGFR inhibition, decreased diabetes-induced oxidative stress, cardiac remodeling, hypertrophy, fibrosis and apoptosis	Liang et al. (2015)
EGFR and its downstream ER stress lead to cardiac injury and microvascular dysfunction in T1D	C57BL/6J	STZ only or in combination with AG1478, tudca or insulin	• AG1478, tudca, and insulin reduced cardiac fibrosis, collagen type I, and plasminogen activator inhibitor 1 and restored the impaired epithelium dependent and independent relaxation responses in T1D mice	Galan et al. (2012)
EGFR contributes to ROS production and cardiac damage	Wistar rats	Aldosterone and EGF	• Aldosterone-induced NHE-1 stimulation, via EGFR transactivation resulted in ROS production and cardiac injury	De Giusti et al. (2011)

T2D, type 2 diabetes; ER, endoplasmic reticulum; I/R, ischemia/reperfusion; Ang II, angiotensin II; STZ, streptozocin; ApoE, apolipoprotein E; ROS, reactive oxygen species; NHE, sodium hydrogen exporter.