on September 2, 2008
Published online before print September 2, 2008, doi: 10.1161/HYPERTENSIONAHA.108.113639
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Submitted on March 17, 2008
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. * To whom correspondence should be addressed. E-mail: robert-felder{at}uiowa.edu.
Abstract—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.
Revised on April 4, 2008
Mitogen-Activated Protein Kinases Mediate Upregulation of Hypothalamic Angiotensin II Type 1 Receptors in Heart Failure Rats
Shun-Guang Wei;
Key words: MAPK • Ang II • AT1 receptor • heart failure • forebrain
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Hypertension 2008 52: 621-622.
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