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(Circulation Research. 2006;99:1004.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Neuronal Angiotensin II Type 1 Receptor Upregulation in Heart Failure

Activation of Activator Protein 1 and Jun N-Terminal Kinase

Dongmei Liu, Lie Gao, Shyamal K. Roy, Kurtis G. Cornish, Irving H. Zucker

From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha.

Correspondence to Irving H. Zucker, PhD, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850. E-mail izucker{at}unmc.edu

Chronic heart failure (CHF) is a leading cause of mortality in developed countries. Angiotensin II (Ang II) plays an important role in the development and progression of CHF. Many of the important functions of Ang II are mediated by the Ang II type 1 receptor (AT₁R), including the increase in sympathetic nerve activity in CHF. However, the central regulation of the AT₁R in the setting of CHF is not well understood. This study investigated the AT₁R in the rostral ventrolateral medulla (RVLM) of rabbits with CHF, its downstream pathway, and its gene regulation by the transcription factor activator protein 1 (AP-1). Studies were performed in 5 groups of rabbits: sham (n=5), pacing-induced (3 to 4 weeks) CHF (n=5), CHF with intracerebroventricular (ICV) losartan treatment (n=5), normal with ICV Ang II treatment (n=5), and normal with ICV Ang II plus losartan treatment (n=5). AT₁R mRNA and protein expressions, plasma Ang II, and AP-1–DNA binding activity were significantly higher in RVLM of CHF compared with Sham rabbits (240.4±30.2%, P<0.01; 206.6±25.8%, P<0.01; 280±36.5%, P<0.05; 207±16.4%, P<0.01, respectively). Analysis of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) pathway showed that phosphorylated c-Jun proteins, phosphorylated JNK proteins, and JNK activity increased significantly in RVLM of CHF compared with sham (262.9±48.1%, 213.8±27.7%, 148.2±10.1% of control, respectively). Importantly, ICV losartan in CHF rabbits attenuated these increases. ICV Ang II in normal rabbits simulated the molecular changes seen in CHF. This effect was blocked by concomitant ICV losartan. In addition, Ang II–induced AT₁R expression was blocked by losartan and a JNK inhibitor, but not by extracellular signal-regulated kinase or p38 MAP kinase inhibitors in a neuronal cell culture. These data suggest that central Ang II activates the AT₁R, SAPK/JNK pathway. AP-1 may further regulate gene expression in RVLM in the CHF state.

Key Words: angiotensin II • sympathetic nerve activity • chronic tachycardia

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