Silencing of cardiac epidermal growth factor receptor reduces cardiac hypertrophy of adult spontaneously hypertensive rat

DÍAZ RG; ESCUDERO DS; MORGAN PE; CALDIZ CI; PÉREZ NG; PORTIANSKY EL; BREA MS

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Simposio; The Fourth South American Symposium in Signal Transduction and Molecular Medicine (SISTAM); 2018

ErbB receptors family is necessary for a normal adult heart function, and is also linked to the generation of several pathologies. Pathological cardiac hypertrophy (PCH) activates epidermal growth factor receptor (EGFR, ErbB1) transactivation. Experimentally, its pharmacological inhibition prevented PCH. The objective of this study was to limit PCH by a specific and localized silencing of cardiac EGFR of spontaneously hypertensive rats (SHR) with small interference RNA (siRNA). Animals were treated with a sequence that inhibits EGFR expression (l-shEGFR, n=7) or with the non-silencing disordered sequence (l-shSCR, n=10). To promote siRNA entry into the heart, it was integrated into the lentivirus genome and injected at two sites of the heart wall. After 30 days, animals were sacrificed and hearts removed. EGFR protein expression was diminished in l-shEGFR vs l-shSCR group, whereas ErbB2 and ErbB4 were not modified. Heart left ventricle was weighted (LVW) and normalized to body weight (BW) and tibia length (TL) revealing that LVW/BW and LVW/TL were reduced in l-shEGFR vs l-shSCR group. This reduction was accompanied by a decrease of the myocytes cross sectional area. Cardiac function was estimated by echocardiography; l-shSCR group showed a significant reduction in fractional shortening at the end of the treatment, while l-shEGFR group showed no changes. Since activation of EGFR pathway induces reactive oxygen species (ROS) production, oxidative stress was evaluated by lipid peroxidation (TBARS) and basal ROS production. Both were reduced in LV of SHR injected with l-shEGFR vs l-shSCR. Finally, Na+/H+ exchanger (NHE1) activity, linked either with HCP or EGFR activation, was evaluated. In l-shEGFR group the activity of NHE1 decreased vs l-shSCR group. These results show that EGFR is necessary for cardiac hypertrophy caused by hypertension; specific blockade of the receptor reduces both oxidative stress and NHE1 activity, limiting the progression of the disease.