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.

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.

• Authors: Minghao Ye, Jan Wysocki, Francisco R Gonzalez-Pacheco, Mahmoud Salem, Karla Evora, Laura Garcia-Halpin, Marko Poglitsch, Manfred Schuster, Daniel Batlle
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 60 Issue 3 Pg. 730-40 (Sep 2012) ISSN: 1524-4563 [Electronic] United States
• PMID: 22777933 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• Leucine
• angiotensin I (1-7)

Topics

• Angiotensin I (metabolism)
• Angiotensin II (metabolism)
• Angiotensin-Converting Enzyme 2
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Disease Models, Animal
• Humans
• Hydrolysis
• Hypertension (metabolism, physiopathology)
• Imidazoles (pharmacology)
• In Vitro Techniques
• Kidney (metabolism)
• Leucine (analogs & derivatives, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Peptide Fragments (metabolism)
• Peptides (pharmacology)
• Peptidyl-Dipeptidase A (drug effects, metabolism, pharmacology)
• Recombinant Proteins (pharmacology)