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.
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.
Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, 320 E Superior, Chicago, IL 60611, USA.
Minghao
M
Ye
Jan
J
Wysocki
Francisco R
FR
Gonzalez-Pacheco
Mahmoud
M
Salem
Karla
K
Evora
Laura
L
Garcia-Halpin
Marko
M
Poglitsch
Manfred
M
Schuster
Daniel
D
Batlle
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D006868:Hydrolysis; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; C556151:DX600 peptide; D007093:Imidazoles; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; C506331:angiotensin I (1-9); D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine; C118790:angiotensin I (1-7)