Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation

Yumei Feng, Xinping Yue, Huijing Xia, Sharell M. Bindom, Peter J. Hickman, Catalin M. Filipeanu, Guangyu Wu, Eric Lazartigues

Research output: Contribution to journalArticle

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Abstract

We recently reported the presence of angiotensin-converting enzyme (ACE)2 in brain regions controlling cardiovascular function; however, the role of ACE2 in blood pressure regulation remains unclear because of the lack of specific tools to investigate its function. We hypothesized that ACE2 could play a pivotal role in the central regulation of cardiovascular function by regulating other renin-angiotensin system components. To test this hypothesis, we generated an adenovirus expressing the human ACE2 cDNA upstream of an enhanced green fluorescent protein (eGFP) reporter gene (Ad-hACE2-eGFP). In vitro characterization shows that neuronal cells infected with Ad-hACE2-eGFP (10 to 100 multiplicities of infection), but not Ad-eGFP (100 multiplicities of infection), exhibit dose-dependent ACE2 expression and activity. In addition, an active secreted form was detected in the conditioned medium. In vivo, Ad-hACE2-eGFP infection (2×10 plaque-forming units intracerebroventricularly) produced time-dependent expression and activity (with a peak at 7 days) in the mouse subfornical organ. More importantly, 7 days after virus infection, the pressor response to angiotensin (Ang) II (200 pmol intracerebroventricularly) was significantly reduced in Ad-hACE2-eGFP-treated mice compared with controls. Furthermore, subfornical organ-targeted ACE2 overexpression dramatically reduced the Ang II-mediated drinking response. Interestingly, ACE2 overexpression was associated with downregulation of the Ang II type 1 receptor expression both in vitro and in vivo. These data suggest that ACE2 overexpression in the subfornical organ impairs Ang II-mediated pressor and drinking responses at least by inhibiting the Ang II type 1 receptor expression. Taken together, our results show that ACE2 plays a pivotal role in the central regulation of blood pressure and volume homeostasis, offering a new target for the treatment of hypertension and other cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)729-736
Number of pages8
JournalCirculation research
Volume102
Issue number6
DOIs
StatePublished - Mar 1 2008

Fingerprint

Subfornical Organ
Angiotensin Type 1 Receptor
Angiotensin II
Drinking
Down-Regulation
Infection
Blood Pressure
Human Adenoviruses
Virus Diseases
Renin-Angiotensin System
Conditioned Culture Medium
Blood Volume
Reporter Genes
angiotensin converting enzyme 2
enhanced green fluorescent protein
Homeostasis
Cardiovascular Diseases
Complementary DNA
Hypertension
Brain

Keywords

  • Adenovirus
  • Blood pressure
  • Brain
  • Carboxypeptidase
  • Gene therapy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. / Feng, Yumei; Yue, Xinping; Xia, Huijing; Bindom, Sharell M.; Hickman, Peter J.; Filipeanu, Catalin M.; Wu, Guangyu; Lazartigues, Eric.

In: Circulation research, Vol. 102, No. 6, 01.03.2008, p. 729-736.

Research output: Contribution to journalArticle

Feng, Yumei ; Yue, Xinping ; Xia, Huijing ; Bindom, Sharell M. ; Hickman, Peter J. ; Filipeanu, Catalin M. ; Wu, Guangyu ; Lazartigues, Eric. / Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. In: Circulation research. 2008 ; Vol. 102, No. 6. pp. 729-736.
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AU - Xia, Huijing

AU - Bindom, Sharell M.

AU - Hickman, Peter J.

AU - Filipeanu, Catalin M.

AU - Wu, Guangyu

AU - Lazartigues, Eric

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