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(Hypertension. 2008;52:679.)
© 2008 American Heart Association, Inc.

Original Articles

Mitogen-Activated Protein Kinases Mediate Upregulation of Hypothalamic Angiotensin II Type 1 Receptors in Heart Failure Rats

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

From the Department of Internal Medicine (S.-G.W., Y.Y., Z.-H.Z., R.M.W., R.B.F.), Neuroscience Program (S.-G.W., R.B.F.), University of Iowa Carver College of Medicine and Veterans Affairs Medical Center (R.M.W., R.B.F.), Iowa City.

Correspondence to Robert B. Felder, MD, University of Iowa College of Medicine, E318-GH, 200 Hawkins Dr, Iowa City, IA 52242. E-mail robert-felder{at}uiowa.edu

In heart failure (HF), angiotensin II type 1 receptor (AT₁-R) expression is upregulated in brain regions regulating sympathetic drive, blood pressure, and body fluid homeostasis. However, the mechanism by which brain AT₁-R are upregulated in HF remains unknown. The present study examined the hypothesis that the angiotensin II (Ang II)–triggered mitogen-activated protein kinases (MAPKs) p44/42, p38, and c-Jun N-terminal kinase contribute to upregulation of the AT₁-R in the hypothalamus of rats with HF. AT₁-R protein, AT₁-R mRNA, and AT₁-R immunoreactivity increased in the paraventricular nucleus of hypothalamus and the subfornical organ of rats with ischemia-induced HF compared with sham-operated controls. Phosphorylated p44/42 MAPK, c-Jun N-terminal kinase, and p38 MAPK also increased in paraventricular nucleus and subfornical organ. A 4-week ICV infusion of the AT₁-R antagonist losartan decreased AT₁-R protein and phosphorylation of p44/42 MAPK, c-Jun N-terminal kinase, and p38 MAPK in the HF rats. A 4-week ICV infusion of the p44/42 MAPK inhibitor PD98059 or the c-Jun N-terminal kinase inhibitor SP600125 significantly decreased AT₁-R protein and AT₁-R immunoreactivity in the paraventricular nucleus and subfornical organ, but the p38 MAPK inhibitor SB203580 did not. Treatment with ICV losartan, PD98059, and SP600125 had no effect on AT₁-R expression by Western blot in sham-operated rats. In untreated HF rats 4 weeks after coronary ligation, a 3-hour ICV infusion of PD98059, SP600125, or losartan reduced AT₁-R mRNA in paraventricular nucleus and subfornical organ. These data indicate that MAPK plays an important role in the upregulation of AT₁-R in the rat forebrain in HF and suggest that Ang II upregulates its own receptor by this mechanism.

Key Words: MAPK • Ang II • AT₁ receptor • heart failure • forebrain

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Brain Angiotensin and Heart Failure: Further Evidence for a Critical Role of Mitogen-Activated Protein Kinases

Roger A.L. Dampney
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