Transforming Growth Factor‐α Acts via Epidermal Growth Factor Receptor to Increase p44/42 Mitogen‐Activated Protein Kinase Signaling and Expression of Excitatory Mediators in the Hypothalamic Paraventricular Nucleus in Rats

Abstract

Myocardial infarction (MI)‐induced heart failure (HF) in rats leads to activation of brain p44/42 mitogen‐activated protein kinase (MAPK) signaling, which may increase proinflammatory cytokine expression and upregulate renin‐angiotensin system (RAS) activity in the brain, contributing to sympathetic excitation. We recently reported (Hypertension, 2019; 74: AP2010) that activation of the epidermal growth factor receptor (EGFR) in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center, increases p44/42 MAPK signaling in rats with HF. Both transforming growth factor (TGF)‐α and TGF‐β1 can activate EGFR and p44/42 MAPK signaling in peripheral tissues. Both are expressed in the PVN. In the present study, we first examined whether HF alters TGF‐α and TGF‐β1 expression in the PVN. Male rats underwent coronary artery ligation (CL) to induce HF or sham surgery, and brains were collected 4 weeks after CL. Compared with sham rats, HF rats had significantly (*P<0.05) increased TGF‐α mRNA expression (1.93±0.83* vs 1.03±0.29, fold change) in the PVN, but TGF‐β1 mRNA expression in the PVN was comparable between HF and sham rats (1.42±0.63 vs 1.01±0.20). We next examined whether TGF‐α increases p44/42 MAPK activity in the PVN via EGFR. Male rats received bilateral PVN microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR or a scrambled siRNA. One week later, these rats received an intracerebroventricular (ICV) injection of TGF‐α (10 μl, 0.1 μg/μl over 5 min) and the brains were collected 4 hours after the TGF‐α injection. Normal rats without any treatments served as control. Compared with control rats, scrambled siRNA+TGF‐α rats had significantly increases in protein levels of phosphorylated p44/42 MAPK (0.70±0.15* vs 0.23±0.11, corrected by total p44/42 MAPK) and in mRNA expression of the proinflammatory cytokines tumor necrosis factor‐α (5.45±2.10* vs 1.24±0.77, fold change) and interleukin‐1β (2.58±0.33* vs 1.00±0.09, fold change), with a tendency toward an increase in mRNA expression of the RAS component angiotensin II type 1a receptor (1.40±0.29 vs 1.02±0.24, P = 0.08, fold change) in the PVN. All of these findings were ameliorated in the EGFR siRNA+TGF‐α rats (by 21–48%), in which EGFR mRNA expression was reduced by 57%. These results indicate that TGF‐α, an endogenous ligand for EGFR, increases in the PVN in HF and may increase p44/42 MAPK signaling, thereby contributing to the augmented inflammation and RAS activity that drives sympathetic excitation in HF.Support or Funding InformationSupported by NIH grant R01HL136149 and the Department of Veterans Affairs.