Yang Yu, Shun-Guang Wei, Zhi-Hua Zhang, Robert M Weiss, Robert B Felder

Brain mitogen-activated protein kinase (MAPK) signaling pathways are activated in heart failure (HF) induced by myocardial infarction and contribute to augmented sympathetic nerve activity. We tested whether silencing brain extracellular signal-regulated kinases 1 and 2 (ERK1/2, also known as p44/42 MAPK) in the hypothalamic paraventricular nucleus (PVN), a forebrain source of presympathetic neurons, would reduce the upregulation of sympatho-excitatory mediators in the PVN and the augmented sympathetic nerve activity in rats with HF. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce HF, with left ventricular dysfunction confirmed by echocardiography. One week after coronary artery ligation or a sham operation, small interfering RNAs (siRNAs) targeting ERK1/2, or a non-targeting control siRNA, was microinjected bilaterally into the PVN. Studies were conducted five-seven days later. Confocal images revealed reduced phosphorylated ERK1/2 immunofluorescence in the PVN of HF rats treated with the ERK1/2 siRNAs compared with HF rats treated with control siRNA. Western blot confirmed significant reductions in both total and phosphorylated ERK1/2 in the PVN of HF rats treated with ERK1/2 siRNAs, along with reduced expression of renin-angiotensin system components and inflammatory mediators. HF rats treated with ERK1/2 siRNAs also had reduced PVN neuronal excitation (fewer Fra-like immunoreactive neurons), lower plasma norepinephrine levels and improved peripheral manifestations of HF, compared with HF rats treated with control siRNAs. These studies demonstrate that ERK1/2 signaling in the PVN plays a pivotal role in mediating sympathetic drive in HF induced by myocardial infarction, and may be a novel target for therapeutic intervention.