Abstract P2010: Silencing Epidermal Growth Factor Receptor Reduces P44/42 Mitogen-Activated Protein Kinase Signaling in the Hypothalamic Paraventricular Nucleus and Ameliorates Sympathetic Excitation in Rats With Heart Failure After Myocardial Infarction

Abstract

The p44/42 mitogen-activated protein kinase (MAPK) signaling pathway is activated in the brain in myocardial infarction (MI)-induced heart failure (HF). Activation of brain p44/42 MAPK signaling can induce endoplasmic reticulum (ER) stress, increase proinflammatory cytokine expression and upregulate renin-angiotensin system (RAS) activity in the brain, contributing to sympathetic excitation. Multiple excitatory agonists (e.g., angiotensin II, aldosterone and pro-inflammatory cytokines) activate brain MAPK signaling in HF, but the mechanisms are poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR), which has recently been shown to mediate MAPK signaling in peripheral cardiovascular tissues. Male rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center. One week later, some rats were euthanized to confirm the effectiveness of EGFR knockdown in PVN. mRNA for EGFR was significantly (*P<0.05) lower in rats that received the EGFR siRNA (0.54±0.17* vs 1.10±0.20, fold change). Other rats underwent coronary artery ligation (CL) to induce HF. Four weeks later, HF rats treated with siRNA for EGFR, compared with HF rats treated with scrambled siRNA, had lower protein levels of phosphorylated p44/42 MAPK (0.20±0.08* vs 0.34±0.06), lower mRNA levels of the ER stress markers BIP (0.77±0.10* vs 1.00±0.12) and ATF4 (0.71±0.14* vs 1.03±0.25), the inflammatory mediators TNF-α (0.73±0.11* vs 1.01±0.15), IL-1β (0.65±0.14* vs 1.02±0.21) and COX-2 (0.71±0.16* vs 1.00±0.14), and the RAS components ACE (0.68±0.26* vs 1.06±0.37) and AT 1a R (0.70±0.11* vs 1.03±0.28) in the PVN, lower urinary norepinephrine levels (28±9* vs 39±7 ng/ml), and improved peripheral manifestations of HF as indicated by reduced right ventricular/body weight and lung/body weight and left ventricular end-diastolic pressure. These results suggest that EGFR in the PVN activates p44/42 MAPK, as well as RAS, neuroinflammation and ER stress, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in the MI-induced HF syndrome.