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.
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 (2x10(6) 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.
Feng
Yumei
Y
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, Tulane University, New Orleans, La 70112, USA.
Yue
Xinping
X
Xia
Huijing
H
Bindom
Sharell M
SM
Hickman
Peter J
PJ
Filipeanu
Catalin M
CM
Wu
Guangyu
G
Lazartigues
Eric
E
D000256:Adenoviridae / Q000187:drug effects; D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure; D045744:Cell Line, Tumor; D003470:Culture Media / Q000378:metabolism; D015536:Down-Regulation; D004327:Drinking Behavior / Q000187:drug effects; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006339:Heart Rate; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013356:Subfornical Organ / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D015854:Up-Regulation
D003470:Culture Media; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D000804:Angiotensin II; D049452:Green Fluorescent Proteins; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2