Abstract 1598: Activated Mitogen-Activated Protein Kinase Contributes to the Up-regulation of Angiotensin Type 1 Receptors in the Brain of Heart Failure Rats
Introduction: In heart failure (HF), expression of the angiotensin type 1 receptor (AT1-R) is upregulated in multiple brain regions critical for regulating sympathetic drive, blood pressure and body fluid homeostasis. However, mechanism by which brain AT1-R is upregulated in HF remains unknown. Angiotensin II-triggered mitogen-activated protein kinase (MAPK) activation is associated with increased brain expression of c-Fos and c-Jun, the major components of transcription factor activator protein 1 (AP-1). Several AP-1 binding sites are found in the regulatory areas of the AT1-R gene.
Hypothesis: ANG II-activated MAPK contributes to up-regulation of AT1-R in the brain of HF rats.
Methods: HF and sham rats were produced by coronary ligation or sham ligation respectively. Rats received the AT1-R antagonist valsartan (30mg/kg/day) in drinking water or no treatment for 6 weeks. MAPK inhibitors were perfused intracerebroventricularly (ICV, 40μl/hr, over 3hrs). AT1-R mRNA was measured in paraventricular nucleus of hypothalamus (PVN) and subfornical organ (SFO) by real time PCR. Phosphorylated MAPK was detected by immunohistochemistry.
Results: Levels (positive neurons) of phospho-MAPK p-p44/42, p-p38 and p-JNK in PVN were significantly (p<0.01, n=6) increased in untreated HF compared with untreated sham (HF vs. sham: 111.4 ± 10.8 vs. 41.4 ± 7.6; 88.8 ± 10.2 vs. 20.7 ± 3.8; 97.6 ± 9.1 vs. 29.8 ± 4.7, respectively). Concentration of AT1-R mRNA in PVN and SFO was also significantly increased (table⇓) in HF vs. sham. Chronic oral treatment with valsartan, or acute ICV treatment with selective MAPK inhibitors (PD98059, 0.025μg/μl; SP600125, 0.1μg/μl; SB203580, 0.05μg/μl) significantly decreased the expression of AT1-R mRNA in PVN and SFO in HF rats.
Conclusion: These data indicate that MAPK activity and expression of AT1-R mRNA is augmented in cardiovascular regions of the brain in HF, and suggest that ANG II-activated MAPK contributes to up-regulation of the AT1-R in HF.