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(Circulation Research. 2008;102:729.)
© 2008 American Heart Association, Inc.

Integrative Physiology

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

From the Department of Pharmacology and Experimental Therapeutics (Y.F., H.X., S.M.B., P.J.H., C.M.F., G.W., E.L.), Louisiana State University Health Sciences Center; and Department of Pulmonary Diseases (X.Y.), Tulane University, New Orleans, La.

Correspondence to Eric Lazartigues, PhD, Louisiana State University Health Sciences Center, School of Medicine, Department of Pharmacology and Experimental Therapeutics, 1901 Perdido St P7-1, New Orleans, LA 70112. E-mail elazar{at}lsuhsc.edu

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 (2x10⁶ 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.

Key Words: adenovirus • carboxypeptidase • brain • blood pressure • gene therapy

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