Question:

Beside activation by its classical ligands, the EGF receptor (EGFR) can also be trans-activated by other hormones. Although this receptor appears to act as an integrator of a variety of extracellular signals, little is known about its cardiac function.

Methodology:

We generated mice with a targeted deletion of EGFR in VSMC and a strong reduction of EGFR expression in cardiomyocytes (referred to as EGFR KO; Schreier et al. Hypertension 2013). The hearts of these transgenic mice were analyzed concerning gene expression (real-time PCR), radical formation (lucigenin chemiluminescence) and contraction (sarcomere shortening).

Results and Conclusion:

EGFR KO mice were viable but showed increased mortality compared to control littermates. Hearts of EGFR KO mice were characterized by hypertrophy without signs of fibrosis. Cardiac mRNA expression of key calcium handling proteins (DHP receptor, RyR2, SERCA2, NCX) was not different between EGFR KO mice and control littermates. However, sarcomere shortening and relengthening were decelerated in cardiomyocytes of EGFR KO mice, whereas fractional shortening was unchanged. Additionally, we detected an increased cardiac expression of NOS1 and NOX4 and increased NADPH oxidase activity. These findings greatly resemble the alterations that we previously found in aged murine hearts resulting in a post-translational modulation of calcium handling and contraction due to increased oxidative and nitrosative stress.

We conclude that the EGFR supports normal contractile function of cardiomyocytes putatively via repression of NOS1- and NOX4-dependent radical formation.