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

Hypertension. 2012 Sep;60(3):730-40. doi: 10.1161/HYPERTENSIONAHA.112.198622. Epub 2012 Jul 9.

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(-6) m) but not by either form of DX600 (10(-5) m). 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism
  • Angiotensin II / metabolism*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Humans
  • Hydrolysis
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Kidney / metabolism
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / metabolism
  • Peptides / pharmacology
  • Peptidyl-Dipeptidase A / drug effects
  • Peptidyl-Dipeptidase A / metabolism*
  • Peptidyl-Dipeptidase A / pharmacology*
  • Recombinant Proteins / pharmacology

Substances

  • 2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid
  • Angiotensin-Converting Enzyme Inhibitors
  • DX600 peptide
  • Imidazoles
  • Peptide Fragments
  • Peptides
  • Recombinant Proteins
  • angiotensin I (1-9)
  • Angiotensin II
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2
  • Leucine
  • angiotensin I (1-7)