ACE2 Activation Promotes Antithrombotic Activity

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2010 Jan 30

PMID 20111697

Citations 89

Authors

Rodrigo A Fraga-Silva

Brian S Sorg

Mamta Wankhede

Casey DeDeugd

Joo Y Jun

Matthew B Baker

Yan Li

Ronald K Castellano

Michael J Katovich

Mohan K Raizada

Anderson J Ferreira

Affiliations

Soon will be listed here.

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.

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References

Kucharewicz I, Chabielska E, Pawlak D, Matys T, Rolkowski R, Buczko W . The antithrombotic effect of angiotensin-(1-7) closely resembles that of losartan. J Renin Angiotensin Aldosterone Syst. 2002; 1(3):268-72. DOI: 10.3317/jraas.2000.041. View

Wang X, Smith P, Hsu M, Ogletree M, Schumacher W . Murine model of ferric chloride-induced vena cava thrombosis: evidence for effect of potato carboxypeptidase inhibitor. J Thromb Haemost. 2006; 4(2):403-10. DOI: 10.1111/j.1538-7836.2006.01703.x. View

Sorg B, Moeller B, Donovan O, Cao Y, Dewhirst M . Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development. J Biomed Opt. 2005; 10(4):44004. DOI: 10.1117/1.2003369. View

Van Leeuwen R, Kol A, Andreotti F, Kluft C, Maseri A, Sperti G . Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells. Circulation. 1994; 90(1):362-8. DOI: 10.1161/01.cir.90.1.362. View

Jagroop I, Mikhailidis D . Angiotensin II can induce and potentiate shape change in human platelets: effect of losartan. J Hum Hypertens. 2000; 14(9):581-5. DOI: 10.1038/sj.jhh.1001102. View

Santos R, Simoes E Silva A, Maric C, Silva D, Machado R, de Buhr I . Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003; 100(14):8258-63. PMC: 166216. DOI: 10.1073/pnas.1432869100. View

Kucharewicz I, Pawlak R, Matys T, Pawlak D, Buczko W . Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7). Hypertension. 2002; 40(5):774-9. DOI: 10.1161/01.hyp.0000035396.27909.40. View

DeDeugd C, Wankhede M, Sorg B . Multimodal optical imaging of microvessel network convective oxygen transport dynamics. Appl Opt. 2009; 48(10):D187-97. DOI: 10.1364/ao.48.00d187. View

Kalinowski L, Matys T, Chabielska E, Buczko W, Malinski T . Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release. Hypertension. 2002; 40(4):521-7. DOI: 10.1161/01.hyp.0000034745.98129.ec. View

10.

Fraga-Silva R, Pinheiro S, Goncalves A, Alenina N, Bader M, Santos R . The antithrombotic effect of angiotensin-(1-7) involves mas-mediated NO release from platelets. Mol Med. 2007; 14(1-2):28-35. PMC: 2078558. DOI: 10.2119/2007-00073.Fraga-Silva. View

11.

Ferreira A, Raizada M . Genomic and proteomic approaches for targeting of angiotensin-converting enzyme2 for cardiovascular diseases. Curr Opin Cardiol. 2008; 23(4):364-9. DOI: 10.1097/HCO.0b013e328303b79b. View

12.

Ferreira A, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L . Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med. 2009; 179(11):1048-54. PMC: 2689912. DOI: 10.1164/rccm.200811-1678OC. View

13.

A Crackower M, Sarao R, Oudit G, Yagil C, Kozieradzki I, Scanga S . Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002; 417(6891):822-8. DOI: 10.1038/nature00786. View

14.

Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J . Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002; 277(17):14838-43. DOI: 10.1074/jbc.M200581200. View

15.

Nishimura H, Tsuji H, Masuda H, Nakagawa K, Nakahara Y, Kitamura H . Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thromb Haemost. 1997; 77(6):1189-95. View

16.

Hernandez Prada J, Ferreira A, Katovich M, Shenoy V, Qi Y, Santos R . Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008; 51(5):1312-7. DOI: 10.1161/HYPERTENSIONAHA.107.108944. View

17.

Pinheiro S, Simoes E Silva A, Sampaio W, Paula R, Mendes E, Bontempo E . Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension. 2004; 44(4):490-6. DOI: 10.1161/01.HYP.0000141438.64887.42. View

18.

Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N . A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87(5):E1-9. DOI: 10.1161/01.res.87.5.e1. View

19.

Huentelman M, Zubcevic J, Katovich M, Raizada M . Cloning and characterization of a secreted form of angiotensin-converting enzyme 2. Regul Pept. 2004; 122(2):61-7. DOI: 10.1016/j.regpep.2004.05.003. View

20.

Maczewski M, Borys M, Kacprzak P, Gdowski T, Kowalewski M, Wojciechowski D . Late ventricular remodeling in non-reperfused acute myocardial infarction in humans is predicted by angiotensin II type 1 receptor density on blood platelets. Int J Cardiol. 2007; 127(1):57-63. DOI: 10.1016/j.ijcard.2007.04.074. View