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Cited by 67Renin-Angiotensin System StudiesCardiovascular, Neuropeptides, and Oxidative Stress ResearchHeart Rate Variability and Autonomic Control

Neuronal Angiotensin II Type 1 Receptor Upregulation in Heart Failure: Activation of Activator Protein 1 and Jun N-Terminal Kinase

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Liu, Dongmei, Gao, Lie, Roy, Shyamal K., Cornish, Kurtis G., Zucker, Irving H.·2006·Circulation Research
DOI 10.1161/01.res.0000247066.19878.93
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Abstract

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 (AT 1 R), including the increase in sympathetic nerve activity in CHF. However, the central regulation of the AT 1 R in the setting of CHF is not well understood. This study investigated the AT 1 R 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). AT 1 R 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 AT 1 R 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 AT 1 R, SAPK/JNK pathway. AP-1 may further regulate gene expression in RVLM in the CHF state.

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  • Various methods are available to generate rabbit heart failure models, including pacing-induced failure, combined aortic insufficiency-induced volume overload and aortic constriction-induced pressure overload, and coronary ligation.

    “Various methods for generating rabbit heart failure models are available including pacing-induced failure (D. Liu, Gao, Roy, Cornish, & Zucker, 2006), combined aortic insufficiency induced volume overload and aortic constriction induced pressure overload (Pogwizd, et al., 1999), and coronary ligation (Maurice, et al., 1999; D. C. White, et al., 2000).”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as D. Liu, et al., 2006

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Authors
Liu, D., Gao, L., Roy, S. K., Cornish, K. G., & Zucker, I. H.
Affiliations
Nebraska Medical Center (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2006-10-27
Volume
99
Issue
9
Pages
1004-1011
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.0000247066.19878.93
OpenAlex
W2114012278
Cited by
67
References
51
Citations by year
2024: 1 · 2021: 2 · 2019: 6 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 9
FWCI
4.50
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (P01HL62222, P01HL062222)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
Keywords
angiotensin II type 1 receptor, chronic heart failure, ventrolateral medulla, AP-1 transcription factor, JNK signaling, c-Jun phosphorylation, losartan, intracerebroventricular administration, angiotensin II, sympathetic activity, pacing-induced heart failure, MAPK signaling, JNK inhibitor
MeSH terms
Angiotensin II, Animals, Body Weight, Cardiac Output, Low, Cell Line, Echocardiography, Heart, Injections, Intraventricular, Male, Neurons, Organ Size, Rabbits, RNA, Messenger, Up-Regulation, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, MAP Kinase Signaling System, Receptor, Angiotensin, Type 1, JNK Mitogen-Activated Protein Kinases

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