P38 MAPK mediates upregulation of cyclooxygenase‐2 in hypothalamic paraventricular nucleus in rats with heart failure

Abstract

Increased cyclooxygenase‐2 (COX‐2) expression in the paraventricular nucleus of hypothalamus (PVN), with synthesis of prostaglandin E2, contributes to augmented sympathetic nerve activity in heart failure (HF) rats. Increasing evidence has linked the expression of COX‐2 to activation of intracellular mitogen‐activated protein kinase (MAPK) pathways. We hypothesized that activation of central MAPK pathways mediates COX‐2 expression in the PVN in HF. Sprague‐Dawley rats underwent coronary ligation to induce HF or sham surgery (SHAM). HF rats were treated for 4 weeks with intracerebroventricular MAPK inhibitors or vehicle. Compared with SHAM, vehicle treated HF rats had increased (*p<0.05) phosphorylated (normalized to total) p44/42 MAPK (0.22±0.02* vs 0.09±0.01; 0.24±0.02* vs 0.11±0.02), p38 MAPK (0.24±0.03* vs 0.12±0.02) and JNK (0.29±0.03* vs 0.15±0.02), increased COX‐2 mRNA (0.10±0.02* vs 0.04±0.01, normalized to GAPDH) in PVN, and increased PVN neuronal excitation (67±5* vs 25±4). A p38 MAPK inhibitor reduced COX‐2 mRNA in the PVN by 43% (p<0.05, vs vehicle), but p44/42 MAPK and JNK inhibitors had no effect. All three inhibitors significantly decreased excitation of PVN neurons. These data indicate that p38 MAPK plays a critical role in HF‐induced COX‐2 expression in PVN, and so may contribute to augmented sympathetic nerve activity in HF. Supported by a VA Merit Review award.