ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension

Cardiovasc Res. 2011 Dec 1;92(3):401-8. doi: 10.1093/cvr/cvr242. Epub 2011 Sep 27.

Abstract

Aims: Angiotensin II (Ang II) has been shown to have both central and peripheral effects in mediating hypertension, for which the hypothalamic paraventricular nucleus (PVN) is an important brain cardio-regulatory centre. Angiotensin-converting enzyme 2 (ACE2) has been identified as a negative regulator of the pro-hypertensive actions of Ang II. Recent findings from our laboratory suggest that Ang II infusion decreases ACE2 expression in the PVN. In the present study, we hypothesized that ACE2 overexpression in the PVN will have beneficial effects in counteracting Ang II-induced hypertension.

Methods and results: Male Sprague-Dawley rats were used in this study. Bilateral microinjection of an adenovirus encoding hACE2 (Ad-ACE2) into the PVN was used to overexpress ACE2 within this region. Mean arterial pressure measured by radiotelemetry was significantly increased after 14 days in Ang II-infused (200 ng/kg/min) rats vs. saline-infused controls (162.9 ± 3.6 vs. 102.3 ± 1.5 mmHg). Bilateral PVN microinjection of Ad-ACE2 attenuated this Ang II-induced hypertension (130.2 ± 5.7 vs. 162.9 ± 3.6 mmHg). ACE2 overexpression also significantly decreased AT(1)R and ACE expression and increased AT(2)R and Mas expression in the PVN. Additionally, ACE2 overexpression in the PVN attenuated the Ang II-induced increase in the expression of the pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-1β and IL-6 in the PVN.

Conclusion: Our findings suggest that attenuation of pro-inflammatory cytokines in the PVN in combination with the shift of the renin-angiotensin system towards the anti-hypertensive axis (ACE2/Ang-(1-7)/Mas) may be responsible for the overall beneficial effects of ACE2 overexpression in the PVN on the Ang II-induced hypertensive response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae / genetics
  • Angiotensin II*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Blood Pressure
  • Disease Models, Animal
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Hypertension / chemically induced
  • Hypertension / enzymology
  • Hypertension / genetics
  • Hypertension / prevention & control*
  • Inflammation Mediators / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Microinjections
  • Paraventricular Hypothalamic Nucleus / enzymology*
  • Peptidyl-Dipeptidase A / biosynthesis*
  • Peptidyl-Dipeptidase A / genetics
  • Proto-Oncogene Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptor, Angiotensin, Type 2 / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Renin-Angiotensin System
  • Telemetry
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Inflammation Mediators
  • Interleukin-1beta
  • Interleukin-6
  • Proto-Oncogene Proteins
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, G-Protein-Coupled
  • Tumor Necrosis Factor-alpha
  • proto-oncogene proteins c-mas-1
  • Angiotensin II
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, rat
  • Angiotensin-Converting Enzyme 2