Murine recombinant angiotensin-converting enzyme 2: Effect on angiotensin II-dependent hypertension and distinctive angiotensin-converting enzyme 2 inhibitor characteristics on rodent and human angiotensin-converting enzyme 2

Minghao Ye, Jan Wysocki, Francisco R. Gonzalez-Pacheco, Mahmoud Salem, Karla Evora, Laura Garcia-Halpin, Marko Poglitsch, Manfred Schuster, Daniel Batlle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

A newly produced murine recombinant angiotensin (Ang)-converting enzyme 2 (ACE2) was characterized in vivo and in vitro. The effects of available ACE2 inhibitors (MLN-4760 and 2 conformational variants of DX600, linear and cyclic) were also examined. When murine ACE2 was given to mice for 4 weeks, a marked increase in serum ACE2 activity was sustainable. In acute studies, mouse ACE2 (1 mg/kg) obliterated hypertension induced by Ang II infusion by rapidly decreasing plasma Ang II. These effects were blocked by MLN-4760 but not by either form of DX600. In vitro, conversion from Ang II to Ang-(1-7) by mouse ACE2 was blocked by MLN-4760 (10-6M) but not by either form of DX600 (10-5M). Quantitative analysis of multiple Ang peptides in plasma ex vivo revealed formation of Ang-(1-9) from Ang I by human but not by mouse ACE2. Both human and mouse ACE2 led to the dissipation of Ang II with formation of Ang (1-7). By contrast, mouse ACE2-driven Ang-(1-7) formation from Ang II was blocked by MLN-4760 but not by either linear or cyclic DX600. In conclusion, sustained elevations in serum ACE2 activity can be accomplished with murine ACE2 administration, thereby providing a strategy for ACE2 amplification in chronic studies using rodent models of hypertension and cardiovascular disease. Human but not mouse ACE2 degrades Ang I to form Ang-(1-9). There are also species differences regarding rodent and human ACE2 inhibition by known inhibitors such that MLN-4760 inhibits both human and mouse ACE2, whereas DX600 only blocks human ACE2 activity.

Original languageEnglish (US)
Pages (from-to)730-740
Number of pages11
JournalHypertension
Volume60
Issue number3
DOIs
StatePublished - Sep 2012

Keywords

  • ACE2
  • angiotensin
  • human
  • hypertension
  • inhibitor
  • mouse
  • recombinant

ASJC Scopus subject areas

  • Internal Medicine

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