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Published on: June 3, 2018
Epidermal Growth Factor Receptor Silencing Blunts the Slow Force Response to Myocardial Stretch
María S Brea1, Romina G Díaz1, Daiana S Escudero1
1Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina.
Background:
Myocardial stretch increases force biphasically: the Frank-Starling mechanism followed by the slow force response (SFR). Based on pharmacological strategies, we proposed that epidermal growth factor (EGF) receptor (EGFR or ErbB1) activation is crucial for SFR development. Pharmacological inhibitors could block ErbB4, a member of the ErbB family present in the adult heart. We aimed to specifically test the role of EGFR activation after stretch, with an interference RNA incorporated into a lentiviral vector (small hairpin RNA [shRNA]-EGFR).
Methods And Results:
Silencing capability of p-shEGFR was assessed in EGFR-GFP transiently transfected HEK293T cells. Four weeks after lentivirus injection into the left ventricular wall of Wistar rats, shRNA-EGFR-injected hearts showed ≈60% reduction of EGFR protein expression compared with shRNA-SCR-injected hearts. ErbB2 and ErbB4 expression did not change. The SFR to stretch evaluated in isolated papillary muscles was ≈130% of initial rapid phase in the shRNA-SCR group, while it was blunted in shRNA-EGFR-expressing muscles. Angiotensin II (Ang II)-dependent Na+/H+ exchanger 1 activation was indirectly evaluated by intracellular pH measurements in bicarbonate-free medium, demonstrating an increase in shRNA-SCR-injected myocardium, an effect not observed in the silenced group. Ang II- or EGF-triggered reactive oxygen species production was significantly reduced in shRNA-EGFR-injected hearts compared with that in the shRNA-SCR group. Chronic lentivirus treatment affected neither the myocardial basal redox state (thiobarbituric acid reactive substances) nor NADPH oxidase activity or expression. Finally, Ang II or EGF triggered a redox-sensitive pathway, leading to p90RSK activation in shRNA-SCR-injected myocardium, an effect that was absent in the shRNA-EGFR group.
Conclusions:
Our results provide evidence that specific EGFR activation after myocardial stretch is a key factor in promoting the redox-sensitive kinase activation pathway, leading to SFR development.
Insights
Myocardial stretch activates epidermal growth factor receptor (EGFR), initiating a redox-sensitive pathway crucial for the slow force response (SFR). Silencing EGFR blunts this response, highlighting its role in cardiac contractility.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Signaling
Background:
- Myocardial stretch elicits a biphasic force increase: the Frank-Starling mechanism and the slow force response (SFR).
- Epidermal growth factor receptor (EGFR) activation is hypothesized to be critical for SFR development.
- The role of specific EGFR activation in response to myocardial stretch requires further elucidation.
Purpose of the Study:
- To investigate the specific role of EGFR activation in the development of the slow force response (SFR) following myocardial stretch.
- To determine if EGFR signaling mediates the redox-sensitive pathways involved in SFR.
Main Methods:
- Utilized lentiviral vectors carrying small hairpin RNA (shRNA) to specifically silence EGFR in Wistar rat hearts.
- Assessed EGFR protein expression, ErbB2 and ErbB4 expression, and SFR in isolated papillary muscles.
- Evaluated Angiotensin II (Ang II)-dependent Na+/H+ exchanger 1 activation, reactive oxygen species (ROS) production, and p90RSK activation.
Main Results:
- shRNA-mediated EGFR silencing significantly reduced EGFR protein expression by approximately 60% without altering ErbB2 or ErbB4 levels.
- EGFR silencing blunted the slow force response (SFR) to myocardial stretch and inhibited Ang II-dependent Na+/H+ exchanger 1 activation.
- Reactive oxygen species (ROS) production triggered by Ang II or EGF was significantly reduced in EGFR-silenced hearts, as was p90RSK activation.
Conclusions:
- Specific EGFR activation following myocardial stretch is a key mediator of the slow force response (SFR).
- EGFR signaling promotes a redox-sensitive kinase activation pathway essential for SFR development.
- Targeting EGFR may offer a therapeutic strategy for modulating cardiac contractility.
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