title: ACE2 activation promotes antithrombotic activity.
abstract: The aim of the present study was to test the hypothesis that the activation of the angiotensin-converting enzyme (ACE)2/angiotensin-(1-7)/Mas receptor axis by use of a novel ACE2 activator (XNT) would protect against thrombosis. Thrombi were induced in the vena cava of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, and ACE2 and ACE activity in the thrombus was determined. Real-time thrombus formation was viewed through intravital microscopy of vessels in nude mice. Thrombus weight was 40% greater in the SHR (4.99 +/- 0.39 versus 7.04 +/- 0.66 mg). This weight increase was associated with a 20% decrease in ACE2 activity in the thrombus. In contrast, there were no differences between the WKY and SHR in ACE2 protein and ACE activity in the thrombi. ACE2 inhibition (DX600; 0.1 micromol/L/kg) increased thrombus weight by 30% and XNT treatment (10 mg/kg) resulted in a 30% attenuation of thrombus formation in the SHR. Moreover, XNT reduced platelet attachment to injured vessels, reduced thrombus size, and prolonged the time for complete vessel occlusion in mice. Thus, a decrease in thrombus ACE2 activity is associated with increased thrombus formation in SHR. Furthermore, ACE2 activation attenuates thrombus formation and reduces platelet attachment to vessels. These results suggest that ACE2 could be a novel target for the treatment of thrombogenic diseases.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida 32610, United States of America.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Fraga-Silva
authors.forename: Brian S
authors.initials: BS
authors.lastname: Sorg
authors.forename: Mamta
authors.initials: M
authors.lastname: Wankhede
authors.forename: Casey
authors.initials: C
authors.lastname: Dedeugd
authors.forename: Joo Y
authors.initials: JY
authors.lastname: Jun
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Baker
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Castellano
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ferreira
mesh_terms: D000704:Analysis of Variance; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D008297:Male; D051379:Mice; D008819:Mice, Nude; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology; D044004:Xanthones / Q000494:pharmacology
chemical_list: C541435:1-((2-dimethylamino)ethylamino)-4-(hydroxymethyl)-7-((4-methylphenyl)sulfonyloxy)-9H-xanthene-9-one; D044004:Xanthones; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2